Pyridyl Alkene and Pyridyl Alkine-Acid Amides as Cytostatics and Immunosuppressives

ABSTRACT

The invention relates to a new pyridyl alkene and pyridyl alkine acid amides according to the general formula (I)  
                 
as well as methods for their production, medicaments containing these compounds as well as their medical use, especially in the treatment of tumors or for immunosuppression.

The invention relates to new pyridine compounds, methods for theirproduction, medicaments containing these compounds as well as their use,especially in the treatment of tumor conditions and/or as cytostaticagents or as immunosuppressive agents.

A pressing need exists for cytostatic therapy to provide newpharmaceuticals and/or medicaments which not only possess a strongactivity, but also exert diminished side effects in comparison to manyclassical cancerostatic agents, whereby treatment of a broad as possiblespectrum of tumors should be made accessible. Furthermore, effectivecytostatic agents for an efficient therapy should be made available.Active ingredients of this type should also be exceptionally suitable inthe mentioned indications for a combination therapy, be it in connectionwith other cytostatic agents or with radiation (for example X-rays,radioactive elements, such as cobalt, or linear accelerator, etc.), withoperative procedures, heat treatment, etc.

In this connection, a strong need also exists to enrich tumor therapywith new compounds for overcoming or preventing resistances for example.

This object was successfully solved in a completely surprising manner bymaking available the pyridyl alkane acid amide derivatives definedbelow.

It was known that various pyridine compounds substituted in a specificmanner have pharmacologically useful properties which lie however incompletely different indication areas.

Thus, ω-pyridyl alkane and/or alkene amides with anti-allergic activityare described in EP 0 210 782 which are referred to as having a5-lipoxygenase-inhibiting and anti-histamine action, wherein the amidecomponents of these compounds contain a piperizine or homopiperizinering and the pyridine ring can be linked together in the 2-, 3- or4-position. JP 63,179,869 describes further pyridyl amides, ω-pyridylalkane and alkene amides as anti-allergic effective substancescontaining a substituted piperidine ring in the amine component. Suchcompounds with the same properties are mentioned in Chem. Pharm. Bull37, 100-105 (1989) and in J. Med. Chem. 1989, 583-593.

Pyridyl ureas, pyridyl thioureas and pyridyl carbonamides, wherein theamide portion is bound over an aryl substituted alkyl chain with apiperidine ring or piprazine ring, are described for example in EP-A-0428 434 or in EP-A-0 512 902 as antagonists of the neurokinin receptorand substance P. Furthermore, pyridyl(alkyl)carbonamides,pyridyl(alkyl)sulfonamides and analogous ureas, wherein the amideportion is bound over an alkyl chain with a piperidine ring aredisclosed in EP-A-0 479 601 as active ingredients with anti-arrhythmicproperties.

In WO 91/15 485, the production of pyridine-3,5-dicarboxylic acid estersand amides as well as their use for the treatment of tumor conditions isdescribed. These compounds differ from the compounds according to theinvention described below in very important structural features, forexample by the dicarboxyl grouping on the pyridine ring or the absenceof the hydrocarbon chain between the pyridine ring and the amidegrouping. The compounds disclosed in WO 89/07 443 in the form ofoptically pure R(−)-Ni-guldipine and further analogous dihydropyridineswith cytotoxic activity have larger structural differences. As comparedto these known compounds, the compounds according to the inventionunexpectedly possess a better activity and a wider spectrum of actiondespite the large structural differences.

Structurally closely related compounds are represented by the piperidinecompounds described in EP-A-0 330 026. However, no 3-pyridyl derivativeswere concretely described and no concrete examples were disclosed inthis publication, aside from a single compound which is described below.These known compounds are distinguished by an anti-cholinesteraseactivity, an anti-amnesia activity as well as activities directedagainst hyperkinesia, senile demensia, mania and Alzheimer's disease.

In view of this art, the finding that the compounds according to thegeneral formula (I) defined below have activities which make themparticularly suitable in an excellent manner for the therapy of tumorillnesses was completely unexpected. The pharmacological finding thatthe compounds according to the invention also possess immunosuppressiveproperties besides cytostatic activity is to be considered as equallysurprising.

Pharmacological test results from which this conclusion must be drawn,as well as the concrete tumor indications and combination possibilitiesare detailed and illustrated in the last part of the description.

Therefore, subject-matter of the invention relates to compounds offormula (I)

wherein

-   R¹ is hydrogen, halogen, cyano, trifluoromethyl, hydroxy, benzyloxy,    aminocarbonyl, carboxy, phenyl, phenoxy, phenylthio, pyridyloxy,    pyridylthio, alkyl, especially C₁-C₆-alkyl, alkenyl, especially    C₃-C₆-alkenyl, alkinyl, especially C₃-C₆-alkinyl, hydroxyalkyl,    especially C₁-C₆-hydroxyalkyl, alkoxy, especially C₁-C₆-alkoxy,    alkenyloxy, especially C₃-C₆-alkenyloxy, alkinyloxy, especially    C₃-C₆-alkinyloxy, alkanoyloxy, especially C₁-C₇-alkanoyloxy,    alkoxycarbonyloxy, especially C₂-C₇-alkoxycarbonyloxy, alkylthio,    especially C₁-C₆-alkylihio, alkenylthio, especially    C₃-C₆-alkenylthio, alkinylthio, especially C₃-C₆-alkinylthio,    cycloalkyl, especially C₃-C₈-cycloalkyl, cycloalkyloxy, especially    C₃-C₈-cycloalkyloxy, cycloalkylthio, especially    C₃-C₈-cycloalkylthio, alkoxycarbonyl, especially    C₂-C₇-alkoxycarbonyl, alkylaminocarbonyl, especially    C₂-C₇-alkylaminocarbonyl, dialkylaminocarbonyl, especially    C₃-C₁₃-dialkylaminocarbonyl, or NR⁵R⁶, wherein-   R⁵ and-   R⁶ are selected independently of each other from hydrogen, alkyl,    especially C₁-C₆-alkyl, alkenyl, especially C₃-C₆-alkenyl and    alkinyl, especially C₃-C₆-alkinyl,-   R² is hydrogen, halogen, cyano, hydroxy, trifluoromethyl, benzyloxy,    alkyl, especially C₁-C₆-alkyl, alkoxy, especially C₁-C₆-alkoxy or    alkanoyloxy, especially C₁-C₇-alkanoyloxy,    -   wherein R¹ and R², if they are adjacent, optionally form a        bridge which is selected from    -   —(CH₂)₄—, —(CH═CH)₂— and —CH₂O—CR⁷R⁸—O—, wherein-   R⁷ and-   R⁸ are, independently of each other, hydrogen or alkyl, especially    C₁-C₆-alkyl,-   R³ is hydrogen, halogen, alkyl, especially C₁-C₆-alkyl,    trifluoromethyl or hydroxyalkyl, especially C₁-C₆-hdroxyalkyl and-   R⁴ is hydrogen, hydroxy, benzyloxy,    -   alkyl, especially C₁-C₆-alkyl,    -   alkenyl, especially C₃-C₆-alkenyl,    -   alkinyl, especially C₃-C₆-alkinyl,    -   cycloalkyl, especially C₃-C₆-cycloalkyl or    -   alkoxy, especially C₁-C₆-alkoxy,-   k is 0 or 1,-   A is alkenylene, especially C₂-C₆-alkenylene, which is optionally    substituted once to three-fold by C₁-C₃-alkyl, hydroxy,    C₁-C₃-alkoxy, fluorine, cyano or phenyl,    -   alkadienylene with at least four C-atoms, especially        C₄-C₆-alkadienylene, which is optionally substituted once or        twice by C₁-C₃-alkyl, fluorine, cyano or phenyl,    -   1,3,5-hexatrienylene, which is optionally substituted by        C₁-C₃-alkyl, fluorine, cyano, or phenyl,    -   ethinylene-   D is selected from alkylene, especially C₁-C₁₀-alkylene, optionally    substituted once or twice by alkyl, especially C₁-C₆-alkyl, hydroxy,    or alkoxy, especially C₁-C₆-alkoxy,    -   alkenylene with at least two C-atoms, especially        C₂-C₁₀-alkenylene, which is optionally substituted once or twice        by alkyl, especially C₁-C₆-alkyl, hydroxy, or alkoxy, especially        C₁-C₆-alkoxy, wherein the double bond can also be to ring E,    -   alkinylene with at least three C-atoms, especially        C₃-C₁₀-alkinylene, optionally substituted once or twice by        alkyl, especially C₁-C₆-alkyl, hydroxy or alkoxy, especially        C₁-C₆-alkoxy, and    -   alkylene, especially C₁-C₁₀-alkylene, alkenylene with at least        two C-atoms, especially C₂-C₁₀-alkenylene or alkinylene with at        least three C-atoms, especially C₃-C₁₀-alkinylene, whereby one        to three methylene units are each isosterically replaced by O,        S, NR⁹, CO, SO or SO₂ wherein-   R⁹ is selected from hydrogen, alkyl, especially C₁-C₆-alkyl,    alkenyl, especially C₃-C₆-alkenyl, alkinyl, especially    C₃-C₆-alkinyl, acyl, especially C₁-C₆-acyl or alkylsulfonyl,    especially C₁-C₆-alkylsulfonyl,-   E is selected from    -   wherein the heterocyclic ring can also optionally have a double        bond and-   n and-   p can be, independently of one another, 0, 1, 2 or 3, with the    proviso that n+p≦4 and-   q is 2 or 3,-   R¹⁰ is hydrogen, alkyl, especially C₁-C₆-alkyl, hydroxy,    hydroxymethyl, carboxy or alkoxycarbonyl with at least two C-atoms,    especially C₂-C₇-alkoxycarbonyl and-   R¹¹ is hydrogen, alkyl, especially C₁-C₆-alkyl or or an oxo group    adjacent to the nitrogen atom, wherein-   R¹⁰ and R¹¹ optionally together, form an alkylene bridge with 1, 2,    3, 4 or 5 C-atoms, especially a C₁-C₃-alkylene bridge under    formation of a bicyclic ring system,-   G is selected from hydrogen,    -   G1, G2, G3, G4 and G5, wherein    -   G1 represents the residue        —(CH₂)_(r)—(CR¹³R¹⁴)_(s)—R¹²  (G1)    -   wherein-   r is an integer from 1 to 3 or 0 and-   s is 0 or 1,-   R¹² is selected from hydrogen, alkyl, especially C₁-C₆-alkyl,    alkenyl with at least three C-atoms, especially C₃-C₆-alkenyl,    alkinyl with at least three C-atoms, especially C₃-C₆-alkinyl,    cycloalkyl with at least three C-atoms, especially C₃-C₈-cycloalkyl,    -   saturated, five to seven membered heterocycles, which can        contain one or two hetero-atoms from the group N and/or S and/or        O,    -   benzyl or phenyl,    -   monocyclic aromatic five or six-membered heterocycles, which can        contain one to three hetero-atoms from the group N and/or S        and/or O and are either bound directly or over a methylene        group,    -   anellated bi- and tricyclic aromatic or partially hydrated        carbocyclic ring systems with 8 to 16 ring atoms and at least        one aromatic ring, wherein the linkage can occur either over an        aromatic or a hydrated ring and either directly or over a        methylene group,    -   anellated bi- and tricyclic aromatic or partially hydrated        heterocyclic ring systems with 8 to 16 ring atoms and at least        one aromatic ring, wherein one to three ring atoms can be        selected from N and/or S and/or O and the linkage can occur        either over an aromatic or a hydrated ring and either directly        or over a methylene group,-   R¹³ has the same meaning as R¹², but is selected independently    thereof,-   R¹⁴ is selected from hydrogen, hydroxy, methyl, benzyl, phenyl,    -   monocyclic aromatic five- or six-membered heterocycles, which        can contain one to three hetero-atoms selected from the group N        and/or S and/or O and are either bound directly or over a        methylene group,    -   anellated bi- and tricyclic aromatic or partially hydrated        carbocyclic ring systems with 8 to 16 ring atoms and at least        one aromatic ring, wherein the linkage can occur either over an        aromatic or a hydrated ring and either directly or over a        methylene group,    -   anellated bi- and tricyclic aromatic or partially hydrated        heterocyclic ring systems with 8 to 16 ring atoms and at least        one aromatic ring, wherein one to three ring atoms can be        selected from N and/or S and/or O and the linkage can occur        either over an aromatic or a hydrated ring and either directly        or over a methylene group,-   G2 is the residue    wherein the substituents R¹² and R¹⁴ can have the above meaning or    the grouping    —NR¹²R¹⁴    -   can also be a nitrogen heterocycle bound over the nitrogen atom,        selected from    -   saturated or unsaturated monocyclic, four- to eight-membered        heterocycles, which, aside from the essential nitrogen atom, can        optionally contain one or two further hetero-atoms selected from        the group N and/or S and/or O, or    -   saturated or unsaturated bi- or tricyclic, anellated or bridged        heterocycles with 8 to 16 ring atoms, which, aside from the        essential nitrogen atom, can optionally contain one or two        further hetero-atoms selected from the group N and/or S and/or        O,-   G3 is the residue    —SO₂—(CH₂)_(r)R¹²  (G3)    -   and-   G4 is the residue    -   wherein-   Ar¹ and Ar² are selected independently from one another from phenyl,    pyridyl or naphthyl and-   G5 is the residue    —COR¹⁵  (G5)    -   wherein-   R¹⁵ is selected from trifluoromethyl, alkoxy, especially    C₁-C₆-alkoxy, alkenyloxy, especially C₃-C₆-alkenyloxy, or benzyloxy,    wherein any aryl residues and/or aromatic ring systems in the    substituents R¹, R², R⁴, R¹², R¹³, R¹⁴, R¹⁵, Ar¹ and Ar² and/or in    the ring system —NR¹²R¹⁴ can be substituted independently from each    other by one to three of the same or different residues which are    selected from halogen, cyano, alkyl, especially C₁-C₆-alkyl,    trifluoromethyl, cycloalkyl, especially C₃-C₈-cycloalkyl, phenyl,    benzyl, hydroxy, alkoxy, especially C₁-C₆-alkoxy, alkoxy,    substituted entirely or partially by fluorine, substituted alkoxy    especially C₁-C₆-alkoxy, benzyloxy, phenoxy, mercapto, alkylthio,    especially C₁-C₆-alkylthio, carboxy, alkoxycarbonyl, especially    C₁-C₆-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino,    monoalkylamino, especially mono-C₁-C₆-alkylamino, dialkylamino,    especially di-(C₁-C₆-alkyl)-amino and methylenedioxy for two    adjacent groups on the aromatic ring or ring system, wherein each of    the residues alkyl, alkenyl, alkinyl, hydroxyalkyl, alkoxy,    alkenyloxy, alkinyloxy, alkanoyloxy, alkoxycarbonyl,    alkoxycarbonyloxy, alkylthio, alkenylthio, alkinylthio, alkylene,    acyl, alkylsulfonyl, alkenylene, alkinylene, cycloalkyl,    cycloalkyloxy, alkoxycarbonyl, alkylaminocarbonyl or    dialkylaminocarbonyl of the substituents R¹ to R¹³ can have 1 to 2    or 4, 6, 8, 10 or 12 C-atoms and/or 2 or 3 to 5, 7, 9, 11 or 13    and/or 15 C-atoms or 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15    C-atoms depending on the structure, as well as    stereoisomers and/or mixtures thereof and pharmacologically    acceptable    acid addition salts thereof    with the exception of    (E)-3-(3-pyridyl)-N-[2-(1-benzylpiperidin-4-yl)ethyl)-2-propenamide    hydrochloride.

A preferred embodiment according to the invention relates to compoundsof formula (I)

wherein

-   R¹ is a hydrogen, halogen, cyano, C₁-C₆-alkyl, C₃-C₆-alkenyl,    C₃-C₆-alkinyl, trifluoromethyl, C₃-C₈-cycloalkyl,    C₁-C₆-hydroxyalkyl, hydroxy, C₁-C₆-alkoxy, C₃-C₆-alkenyloxy,    C₃-C₆-alkinyloxy, benzyloxy, C₁-C₇-alkanoyloxy,    C₂-C₇-alkoxycarbonyloxy, C₁-C₆-alkylthio, C₃-C₆-alkenylthio,    C₃-C₆-alkinylthio, C₃-C₈-cycloalkyloxy, C₃-C₈-cycloalkylthio,    C₂-C₇-alkoxycarbonyl, aminocarbonyl, C₂-C₇-alkylaminocarbonyl,    C₃-C₁₃-dialkylaminocarbonyl, carboxy, phenyl, phenoxy, phenylthio,    pyridyloxy, pyridylthio, or NR⁵R⁶, wherein-   R⁵ and-   R⁶ are selected independently from each other from hydrogen,    C₁-C₆-alkyl, C₃-C₆-alkenyl and C₃-C₆-alkinyl,-   R² is hydrogen, halogen, cyano, C₁-C₆-alkyl, trifluoromethyl,    hydroxy, C₁-C₆-alkoxy, benzyloxy or C₁-C₇-alkanoyloxy,    -   wherein R¹ and R², in case they are adjacent, optonally form a        bridge which is selected from the bridge members    -   —(CH₂)₄— and —(CH═CH)₂— and —CH₂O—CR⁷R⁸—O—, wherein-   R⁷ and-   R⁸ are, independently from each other, hydrogen or C₁-C₆-alkyl,-   R³ is hydrogen, halogen, C₁-C₆-alkyl, trifluoromethyl or    C₁-C₆-hydroxyalkyl and-   R⁴ is hydrogen, C₁-C₆-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkinyl,    C₃-C₆-cycloalkyl, hydroxy, C₁-C₆-alkoxy or benzyloxy,-   k is 0 or 1,-   A is C₂-C₆-alkenylene, which is optionally substituted once to    three-fold by C₁-C₃-alkyl, hydroxy, C₁-C₃-alkoxy, fluorine, cyano or    phenyl,    -   C₄-C₆-alkadienylene, which is optionally substituted once or        twice by C₁-C₃-alkyl, fluorine, cyano or phenyl    -   1,3,5-hexatrienylene, which is optionally substituted by        C₁-C₃-alkyl, fluorine, cyano or phenyl as well as    -   ethinylene,-   D is selected from C₁-C₁₀-alkylene, optionally substituted once or    twice by C₁-C₆-alkyl, hydroxy, or C₁-C₆-alkoxy,    -   C₂-C₁₀-alkenylene, which is optionally substituted once or twice        by C₁-C₆-alkyl, hydroxy, or C₁-C₆-alkoxy, wherein the double        bond can also be to ring E,    -   C₃-C₁₀-alkinylene, optionally substituted once or twice by        C₁-C₆-alkyl, hydroxy, or C₁-C₆-alkoxy, and    -   C₁-C₁₀-alkylene, C₂-C₁₀-alkenylene or C₃-C₁]-alkinylene, wherein        one to three methylene units are each isosterically replaced by        O, S, NR⁹, CO, SO or SO₂, wherein-   R⁹ is selected from hydrogen, C₁-C₆-alkyl, C₃-C₆-alkenyl,    C₃-C₆-alkinyl, C₁-C₆-acyl or C₁-C₆-alkylsulfonyl,    -   E is selected from    -   wherein the heterocyclic ring can optionally have a double bond        and-   n and-   p can be, independently of each other, 0, 1, 2 or 3, with the    proviso that n+p≦4 and-   q is 2 or 3,-   R¹⁰ is hydrogen, C₁-C₆-alkyl, hydroxy, hydroxymethyl, carboxy or    C₂-C₇-alkoxycarbonyl and-   R¹¹ hydrogen, C₁-C₆-alkyl or an oxo group adjacent to the nitrogen    atom, wherein-   R¹⁰ and R¹¹ optionally together form a C₁-C₃-alkylene bridge under    formation of a bi-cyclic ring system,-   G is selected from hydrogen,    -   G1, G2, G3, G4 and G5, wherein    -   G1 represents the residue        —(CH₂)_(r)—(CR¹³R¹⁴)_(s)—R¹²  (G1) (G1)    -   wherein-   r is an integer from 1 to 3 or O and-   s is 0 or 1,-   R¹² is selected from hydrogen, C₁-C₆-alkyl, C₃-C₆-alkenyl,    C₃-C₆-alkinyl, C₃-C₈-cycloalkyl,    -   saturated, five- to seven-membered heterocycles, which can        contain one or two hetero-atoms from the group N and/or S and/or        O,    -   benzyl or phenyl,    -   monocyclic aromatic five or six-membered heterocycles, which can        contain one to three hetero-atoms from the group N and/or S        and/or O and are either bound directly or over a methylene        group.    -   anellated bi- and tricyclic aromatic or partially hydrated        carbocyclic ring systems with 8 to 16 ring atoms and at least        one aromatic ring, wherein the linkage can occur either over an        aromatic or a hydrated ring and either directly or over a        methylene group,    -   anellated bi- and tricyclic aromatic or partially hydrated        heterocyclic ring systems with 8 to 16 ring atoms and at least        one aromatic ring, wherein one to three ring atoms can be        selected from N and/or S and/or O and the linkage can occur        either over an aromatic ring or a hydrated ring and either        directly or over a methylene group,-   R¹³ has the same meaning as R¹², but is selected independently    thereof,-   R¹⁴ is selected from hydrogen, hydroxy, methyl, benzyl, phenyl,    -   monocyclic aromatic five or six-membered heterocycles, which can        contain one to three hetero-atoms selected from the group N        and/or S and/or O and are either bound directly or over a        methylene group,    -   anellated bi- and tricyclic aromatic or partially hydrated        carbocyclic ring systems with 8 to 16 ring atoms and at least        one aromatic ring, wherein the linkage can occur either over an        aromatic or a hydrated ring and either directly or over a        methylene group,    -   anellated bi- and tricyclic aromatic or partially hydrated        heterocyclic ring systems with 8 to 16 ring atoms and at least        one aromatic ring, wherein one to three ring atoms can be        selected from N and/or S and/or O and the linkage can occur        either over an aromatic ring or a hydrated ring and either        directly or over a methylene group,        G2 is the residue    -   wherein the substituents R¹² and R¹⁴ can have the above meaning        or the grouping        —NR¹²R¹⁴    -   can also be a nitrogen heterocycle bound over the nitrogen atom,        selected from    -   saturated or unsaturated monocyclic, four- to eight-membered        heterocycles, which, aside from the essential nitrogen atom, can        optionally contain one or two further hetero-atoms selected from        the group N and/or S and/or O, or    -   saturated or unsaturated bi- or tricyclic, anellated or bridged        heterocycles with 8 to 16 ring atoms, which, aside from the        essential nitrogen atom, can optionally contain one or two        further hetero-atoms selected from the group N and/or S and/or        O,-   G3 is the residue    —SO₂—(CH₂)_(r)R¹²  (G3)

and

-   G4 is the residue    -   wherein-   Ar¹ and Ar² are selected independently from one another from phenyl,    pyridyl or naphthyl and-   G5 is the residue    —COR¹⁵  (G5)    -   wherein-   R¹⁵ is selected from trifluoromethyl, C₁-C₆-alkoxy,    C₃-C₆-alkenyloxy, or benzyloxy, and wherein    aromatic ring systems in the substituents R¹, R², R⁴, R¹², R¹³, R¹⁴,    R¹⁵, Ar¹ and Ar² and/or in the ring system —NR¹²R¹⁴ can be    substituted independently from each other by one to three of the    same or different residues which are selected from halogen, cyano,    C₁-C₆-alkyl, trifluoromethyl, C₃-C₈-Cycloalkyl, phenyl, benzyl,    hydroxy, C₁-C₆-alkoxy, which can optionally be entirely or partially    substituted by fluorine, benzyloxy, phenoxy, mercapto,    C₁-C₆-alkylthio, carboxy, C₁-C₆-alkoxycarbonyl, benzyloxycarbonyl,    nitro, amino, mono-C₁-C₆-alkylamino or di-(C₁-C₆-alkyl)-amino and    methylenedioxy for two adjacent groups on the aromatic ring or ring    system,    stereoisomers thereof and/or mixtures thereof and pharmacologically    acceptable    acid addition salts    with the exception of    (E)-3-(3-pyridyl)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-propenamide    hydrochloride.

A further preferred embodiment of the invention constitutes compounds ofthe invention, which are distinguished in that substituents R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹², R¹³, R¹⁴ and R¹⁵ as well as A and Dlabelled therein have the following meaning in connection with the givensubstitutions according to this formula

wherein

halogen is fluorine, chlorine, bromine or iodine,

C₁-C₆-alkyl can be straight chain or branched and is preferably amethyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, sec-butyl-,tert-butyl-, cyclopropylmethyl-, pentyl-, isopentyl-, tert-pentyl-,neopentyl-, cyclopropylethyl-, cyclobutylmethyl- or a hexyl group,

alkylene is for example methylene, ethylene, propylene, tetramethylene,pentamethylene, hexamethylene, heptamethylene, octamethylene,nonamethylene or decamethylene,

C₃-C₆-alkenyl can be straight chain or branched and is preferably anallyl-, 2-butenyl-, 3-butenyl-, 2-methyl-2-propenyl-, 2-pentenyl-,4-pentenyl-, 2-methyl-2-butenyl-, 3-methyl-, 2-butenyl-, 2-hexenyl-,5-hexenyl-, 4-methyl-3-pentenyl- or 2,2-dimethyl-3-butenyl group,

alkenylene is for example ethenylene, propenylene, butenylene,pentenylene, hexenylene, hexathenylene, heptenylene, octenylene,nonenylene or decenylene,

C₃-C₆-alkinyl can be straight chain or branched and is preferably apropargyl-, 2-butinyl-, 3-butinyl-, 4-pentinyl-, 5-hexinyl- or4-methyl-2-pentinyl group,

alkinylene is for example propinylene, butinylene, pentinylene,hexinylene, heptinylene, octinylene, noninylene or decinylene,

C₃-C₈-cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl or cyclooctyl,

C₁-C₆-hydroxyalkyl contains a hydroxyl group in one of the above-namedC₁-C₆-alkyl residues, especially in the form of the hydroxymethyl- andhydroxyethyl group, wherein

C₁-C₆-alkoxy, C₃-C₆-alkenyloxy, C₃-C₆-alkinyloxy each contain, asidefrom the oxygen atom, one of the C₁-C₆-alkyl-, C₃-C₆-alkenyl- and/orC₃-C₆-alkinyl groups named above and the methoxy-, ethoxy-, isopropoxy-,tert-butoxy-, allyloxy- and propargyloxy group are preferred and is tobe understood as among C₁-C₆-alkoxy entirely or partially substitutedwith fluorine, for example difluormethoxy, trifluormethoxy or2,2,2-trifluorethoxy,

C₁-C₆-alkylthio, C₃-C₆-alkenylthio, C₃-C₆-alkinylthio each contain,aside from the sulfur atom, one of the C₁-C₆-alkyl-, C₃-C₆-alkenyl- orC₃-C₆-alkinyl group named above, especially the methylthio-, ethylthio-,isopropylthio- and tert-butylthio groups,

C₃-C₈-cycloalkyloxy and C₃-C₈-cycloalkylthio are preferred ascyclopentyloxy- and cyclopentylthio- and/or cylohexyloxy- andcyclohexylthio groups,

C₁-C₇-alkanoyloxy groups contain, aside from the oxygen atom, analiphatic acyl, residue with 1 to 7 carbon atoms, especially theacetoxy-, propionyloxy- and pivaloyloxy group,

C₂-C₇-alkoxycarbonyl groups contain, aside from the carbonyl group, oneof the C₁-C₆-alkoxy groups mentioned above, especially themethoxycarbonyl-, ethoxycarbonyl-, isopropoxycarbonyl-,isobutoxycarbonyl- and tert-butoxycarbonyl group,

C₂-C₇-alkoxycarbonyloxy groups contain, aside from the oxygen atom, oneof the C₂-C₇-alkoxycarbonyl residues mentioned above, especially themethoxycarbonyloxy-, ethoxycarbonyloxy-, isopropoxycarbonyloxy-,isobutoxycarbonyloxy- and tert-butoxycarbonyl group as well as theallyloxycarbonyloxy group,

C₂-C₇-alkylaminocarbonyl and C₃-C₁₃-dialkylaminocarbonyl groups contain,beside the carbonyl group, an alkylamino and/or dialkylamino residue,whose C₁-C₆-alkyl groups have the above meanings, wherein thedimethylaminocarbonyl-, diethylaminocarbonyl- and thediisopropylaminocarbonyl groups are preferred, and aside from theunsubstituted amino group, one of the following C₁-C₆-alkylamino groupsand/or di-(C₁-C₆-alkyl)amino groups are to be understood under the aminogroups of the formula NR⁵R⁶,

C₁-C₆-alkylamino contains one of the C₁-C₆-alkyl groups mentioned above,especially in form of the methylamino-, ethylamino-, propylamino-,isopropylamino-, butylamino- and the tert-butylamino group,

di-(C₁-C₆-alkyl)amino carries two of the same or different of the abovenamed C₁-C₆-alkyl groups on the nitrogen atom, especially in form of thedimethylamino-, diethylamino-, dipropylamino-, diisopropylamino-,isopropylmethylamino-, dibutylamino- or tert-butylmethylamino group,

C₁-C₆-acyl is the residue of an aliphatic saturated or unsaturated,straight chain, branched or cyclic carboxylic acid, especially in formof the formyl-, acetyl-, propionyl-, acryloyl-, butyryl-, isobutyryl-,methacryloyl-, cyclopropylcarbonyl-, pentanoyl-, pivaloyl-,cyclobutylcarbonyl-, hexanoyl- and the dimethylacryloyl group,

C₁-C₆-alkansulfonyl is preferably the methanesulfonyl-, ethanesulfonyl-,propanesulfonyl-, butanesulfonyl-, pentanesulfonyl- and thehexanesulfonyl group,

saturated five to seven-membered heterocycles with one or twohetero-atoms are especially tetrahydrofuryl, tetrahydrothienyl,pyrrolidinyl, tetrahydropyranyl, piperidinyl, hexahydroazepinyl,piperazinyl, hexahydrodiazepinyl or morpholinyl,

monocyclic aromatic five- or six-membered heterocycles with one to threehetero-atoms are especially furyl, thienyl, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl,thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl ortriazinyl,

anellated bi- and tricyclic aromatic or partially hydrated carbocyclering systems with 8 to 16 ring atoms and at least one aromatic ring arepreferably benzocyclobutyl, indanyl, indenyl, naphthyl, dihydronaphthyl,tetrahydronaphthyl, biphenylenyl, fluorenyl, anthryl, dihydroanthryl,phenanthryl, dihydrophenanthryl, dibenzocycloheptenyl,dihydrodibenzocycloheptenyl, dihydrodibenzocyclooctenyl ortetrahydrodibenzocyclooctenyl, wherein mono- or dioxo-derivates, whereinthe residues of indanone, tetralone, anthrone, anthraquinone,fluorenone, phenanthrone, dibenzocycloheptenone,dihydrodibenzocycloheptenone or tetrahydrodibenzocyclooctenone are forexample also to be understood as partially hydrated carbocyclic ringsystems,

anellated bi- and tricyclische aromatic or partially hydratedheterocyclic ring systems with 8 to 16 ring atoms and at least onearomatic ring are, for example, imidazothiazolyl, benzofuryl,dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl, indolyl,indolinyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl,benzo-thiazolyl, benzoisothiazolyl, benzofurazanyl, benzothiadiazolyl,benzotriazolyl, oxazolopyridyl, thiazolopyridyl, isothiazolopyridyl,imidazopyridyl, pyrazolopyridyl, thienopyrimidinyl, chromanyl,benzopyranyl, quinolyl, isoquinolyl, dihydroquinolyl,tetrahydroquinolyl, benzodioxanyl, quinoxalinyl, quinazolinyl,naphthyridinyl carbazolyl, tetrahydrocarbazolyl, pyridoindolyl,acridinyl, pbenothiazinyl, dihydrodibenzoxepinyl,benzocycloheptathienyl, dihydrothienobenzothiepinyl,dihydrodibenzothiepinyl, octahydrodibenzothiepinyl,dihydrodibenzazepinyl, octahydrodibenzazepinyl, benzocycloheptapyridyl,dihydropyridobenzodiazepinyl, dihydrodibenzoxazepinyl,dihydropyridobenzoxepinyl, dihydropyridobenzoxazepinyl,dihydrodibenzothiazepinyl or dihydropyridobenzothiazepinyl, whereintheir mono- or dioxo-derivates and/or optionally their possibletautomeres are also to be understood as partially hydrated heterocyclicring systems, for example, the residues of indolinone, isatin,benzoxazolone and/or its tautomeres hydroxybenzoxazol, ofbenzisoxazolone, benzothiazolone, benzoisothiazolone and benzimidazoloneand/or their tautomeres, hydroxybenzisoxazol, hydroxybenzothiazol,hydroxybenzoisothiazol and hydroxybenzimidazol, of indazolinone, ofoxazolopyridinone, thiazolopyridinones, pyrazolopyridinones andimidazopyridinones and/or their tautomeres hydroxyoxazolopyridine,hydroxythiazolopyridines, hydroxypyrazolopyridines andhydroxyimidazopyridines, the residues of chromanone, chromone,quinolinone, di-hydroquinolinone, tetrahydrocarbazolone, acridone, ofdihydrodibenzoxepinones, benzocycloheptathiophenones,dihydrothienobenzothiepinones, dihydrodibenzothiepinones,dihydrodibenzoazepinones, benzocycloheptapyridinones,dihydropyridobenzoxazepinones, dihydrodibenzothiazepinones and ofdihydropyridobenzothiazepinones,

saturated and unsaturated monocyclic, four- to eight-memberedheterocycles represent —NR¹²R¹⁴ as a grouping which, aside from theessential nitrogen atom, can optionally contain one or two furtherhetero-atoms selected from N and/or S and/or O, for example azetidine,pyrrolidine, piperidine, (1H)tetrahydropyridine, hexahydroazepine,(1H)tetrahydroazepine, octahydroazocine, pyrazolidine, piperazine,hexahydrodiazepine, morpholine, hexahydrooxazepine, thiomorpholine orthiomorpholine-1,1-dioxide,

saturated or unsaturated bi- or tricyclic, anellated or bridgedheterocycles with 8 to 16 ring atoms, represent —NR¹²R¹⁴ as a groupingwhich, aside from the essential nitrogen atom optionally contain one ortwo further hetero-atoms, selected from N and/or S and/or O, for example5-aza-bicyclo[2.1.1]hexane, 2-aza-bicyclo[2.2.1]heptane,7-aza-bicyclo[2.2.1]heptane, 2,5-diaza-bicyclo[2.2.1]heptane,2-aza-bicyclo[2.2.2]octane, 8-aza-bicyclo[3.2.1]octane,2,5-diaza-bicyclo[2.2.2]octane, 9-aza-bicyclo[3.3.1]nonane, indoline,isoindoline, (1H)-dihydroquinoline, (1H)-tetrahydroquinoline,(2H)-tetrahydroisoquinoline, (1H)-tetrahydroquinoxaline,(4H)-dihydrobenzoxazine, (4H)-dihydrobenothiazine,(1H)-tetrahydrobenzo[b]azepine, (1H)-tetrahydrobenzo[c]azepine,(1H)-tetrahydrobenzo[d]azepine, (5H)-tetrahydrobenzo[b]oxazepine,(5H)-tetrahydrobenzo[b]thiazepine,1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol, (10H)-dihydroacridine,1,2,3,4-tetrahydroacridanone, (10H)-phenoxazin, (10H)-phenothiazine,(5H)-dibenzazepine, (5H)-dihydrodibenzazepine,(5H)-octahydrodibenzazepine, (5H)-dihydrodibenzodiazepine,(11H)-dihydrodibenzo[b,e]oxazepine, (11H)-dihydrodibenzo[b,e]thiazepine,(10H)-dihydro-dibenzo[b,f]oxazepine, (10H)-dihydrodibenzo[b,f]thiazepineor (5H)-tetrahydrodibenzazocine, as well as typical

tautomeres in the case of substitution of the heterocycle as such or inan anellated ring system by free hydroxy-, mercapto- and/or aminogroups, and

stereoisomers such as, if applicable, cis/trans-isomers,endo/exo-isomers, optic isomers such as enantiomers, diastereomers aspure isomers or mixtures and/or racemic mixtures as well as thepharmacologically acceptable acid addition salts with inorganic ororganic acids, wherein the hydrochlorides, hydrobromides, hydroiodides,sulfates and phosphates, are preferred as addition salts with suitableinorganic acids and acetates, benzoates, citrates, fumarates,gluconates, malates, maleates, methanesulfonates, lactates, oxalates,succinates, tartrates and tosylates are preferred as addition salts oforganic acids.

Compounds in which the substitutents labelled in formula (I)

have the following meanings, are especially preferred:

-   R¹ is hydrogen, halogen, cyano, C₁-C₆-alkyl, trifluoromethyl,    C₃-C₈-cycloalkyl, C₁-C₄-hydroxyalkyl, hydroxy, C₁-C₄-alkoxy,    benzyloxy, C₁-C₄-alkanoyloxy, C₁-C₄-alkylthio, C₂-C₅-alkoxycarbonyl,    aminocarbonyl, C₃-C₉-dialkylaminocarbonyl, carboxy, phenyl, phenoxy,    pyridyloxy or NR⁵R⁶, wherein-   R⁵ and-   R⁶ are selected independently from each other form hydrogen and    C₁-C₆-alkyl,-   R² is hydrogen, halogen, C₁-C₆-alkyl, trifluoromethyl or hydroxy,    wherein-   R¹ and R², in the case they are adjacent, optionally form a bridge    which are selected from the group of bridge members —(CH₂)₄— and    —(CH═CH)₂— and —CH₂O—CR⁷R⁸—O—, wherein-   R⁷ and-   R⁸ can be, independently from each other, hydrogen and C₁-C₆-alkyl,-   R³ is selected from hydrogen, halogen and C₁-C₆-alkyl and-   R⁴ is selected from hydrogen, C₁-C₆-alkyl, C₃-C₆-alkenyl, hydroxy,    C₁-C₆-alkoxy and benzyloxy,-   k is 0 or 1,-   A is C₂-C₆-alkenylene, which is optionally substituted one to    three-fold by C₁-C₃-alkyl, hydroxy, fluorine, cyano, or phenyl,    -   C₄-C₆-alkadienylene, which is optionally substituted once or        twice by C₁-C₃-alkyl, fluorine, cyano, or phenyl,    -   1,3,5-hexatrienylene, which is optionally substituted by        C₁-C₃-alkyl, fluorine, or cyano, as well as    -   ethinylene-   D is selected from C₁-C₁₀-alkylene, which is optionally substituted    once or twice by C₁-C₃-alkyl or hydroxy,    -   C₂-C₁₀-alkenylene, optionally substituted once or twice by        C₁-C₃-alkyl or hydroxy, wherein the double bond can also be to        ring E or    -   C₃-C₁₀-alkinylene, which is optionally substituted once or twice        by C₁-C₃-alkyl or hydroxy, and can be selected as well from    -   C₁-C₁₀-alkylene, C₂-C₁₀-alkenylene or C₃-C₁₀-alkinylene, in        which one to three methylene units are isosterically replaced by        O, S, NR⁹, CO, SO or SO₂, wherein-   R⁹ is hydrogen, C₁-C₃-alkyl, C₁-C₆-acyl or methanesulfonyl,-   E is    -   wherein the heterocyclic ring can optionally have a double bond        and-   n and p can be, independent of each other, 0, 1, 2 or 3, with the    proviso that n+p≦4,-   q is 2 or 3,-   R¹⁰ is selected from hydrogen, C₁-C₃-alkyl, hydroxy, hydroxymethyl,    carboxy or C₂-C₇-alkoxycarbonyl and-   R¹¹ is selected from hydrogen or an oxo group adjacent to the    nitrogen atom,-   G is selected from hydrogen,    -   G1, G2, G3, G4 and G5, wherein-   G1 represents the residue    —(CH₂)_(r)—(CR¹³R¹⁴)_(s)—R¹²  (G1)    -   wherein-   r is 0, 1 or 2 and-   s is 0 or 1,-   R¹² is selected from hydrogen, C₁-C₆-alkyl, C₃-C₆-alkenyl,    C₃-C₆-alkinyl, C₃-C₈-cycloalkyl,    -   benzyl, phenyl,    -   monocyclic aromatic five- or six-membered heterocycles, which        contain one to three hetero-atoms from the group N and/or S        and/or O and are either bound directly or over a methylene        group,    -   anellated bi- and tricyclic aromatic or partially hydrated        carbocyclic ling systems with 8 to 16 ring atoms and at least        one aromatic ring, whereby the bond can occur either over an        aromatic or a hydrated ring and either directly or over a        methylene group,    -   anellated bi- and tricyclic somatic or partially hydrated        heterocyclic ring systems with 8 to 16 ring atoms and at least        one aromatic ring, wherein one to three ring atoms can be        selected from the groups N and/or S and/or O and the bond can        occur either over an aromatic or a hydrated ring and either        directly or over a methylene group,-   R¹³ has the same meaning as R¹², but is selected independently    thereof,-   R¹⁴ is selected from hydrogen, hydroxy, methyl, benzyl or phenyl,    -   monocyclic aromatic five- or six-membered heterocycles, which        can contain one to three hetero-atoms selected from the group N        and/or S and/or O and are bound either directly or over a        methylene group,    -   anellated bi- and tricyclic aromatic or partially hydrated        carbocyclic ring systems with 8 to 16 ring atoms and at least        either aromatic ring, wherein the bond can occur either over an        aromatic or a hydrated ring and either directly or over a        methylene group,    -   anellated bi- and tricyclic aromatic or partially hydrated        heterocyclic ring systems with 8 to 16 ring atoms and at least        one aromatic ring, wherein one to three ring atoms can be        selected from the group N and/or S and/or O and the bond can        occur either over an aromatic or a hydrated ring and either        directly or over a methylene group,-   G2 is selected from the residues    -   wherein the substituents R¹² and R¹⁴ the can have the above        meaning, or the grouping        —NR¹²R¹⁴    -   can also be a nitrogen heterocycle bound over the nitrogen atom,        selected from    -   saturated or unsaturated monocyclic, four- to eight-membered        heterocycles, which, aside from the essential nitrogen atom, can        optionally contain one or two further hetero-atoms selected from        N and/or S and/or O, or    -   saturated or unsaturated bi- or tricyclic, anellated or bridged        heterocycles with 8 to 16 ring atoms, which, aside from the        essential nitrogen atom, can optionally contain one or two        further hetero-atoms selected from N and/or S and/or O,-   G3 is the residue    —SO₂—(CH₂)_(r)R¹²  (G3),-   G4 is the residue    -   wherein-   Ar¹ and-   Ar² are selected independently of each other from phenyl, pyridyl or    naphthyl,-   G5 is the residue    —COR¹⁵  (G5)    -   wherein-   R¹⁵ is trifluoromethyl, C₁-C₆-alkoxy, C₃-C₆-alkenyloxy or benzyloxy    and    -   aromatic ring systems in which the substituents R¹, R², R⁴, R¹²,        R¹³, R¹⁴, R¹⁵, Ar¹ and Ar² and/or in the ring system —NR¹²R¹⁴        can carry independently of each other one to three of the same        or different substituents from the series halogen, cyano,        C₁-C₆-alkyl, trifluoromethyl, C₃-C₈-cycloalkyl, phenyl, benzyl,        hydroxy, C₁-C₆-alkoxy, which can be optionally entirely or        partially substituted by fluorine, benzyloxy, phenoxy, mercapto,        C₁-C₆-alkyl-thio, carboxy, C₁-C₆-alkoxycarbonyl,        benzyloxycarbonyl, nitro, amino, mono-C₁-C₆-alkylamino,        di-(C₁-C₆-alkyl)-amino, wherein two adjacent groups on the        aromatic ring or ring system can form an additional ring over a        methylenedioxy bridge.

Compounds in which the substitutents labelled in formula (I)

have the following meanings are particularly preferred:

-   R¹ is hydrogen, halogen, cyano, methyl, trifluoromethyl, hydroxy,    C₁-C₄-alkoxy, ethylthio, methoxycarbonyl, tert-butoxycarbonyl,    aminocarbonyl, carboxy, and phenoxy,-   R² is hydrogen, halogen, trifluoromethyl or hydroxy,-   R³ is hydrogen or halogen,-   R⁴ is selected from hydrogen, C₁-C₃-alkyl, hydroxy and C₁-C₃-alkoxy,-   k is or 1,-   A is C₂-C₆-alkenylene, which is optionally substituted once or twice    by C₁-C₃-alkyl, hydroxy or fluorine, or    -   C₄-C₆-alkadienylene, which is optionally substituted by is        C₁-C₃-alkyl or by 1 or 2 fluorine atoms, or    -   1,3,5-hexatrienylene, which is optionally substituted by        fluorine, as well as-   D is C₁-C₈-alkylene, which is optionally substituted once twice by    methyl or hydroxy,    -   C₂-C₈-alkenylene, which is optionally substituted once or twice        by methyl or hydroxy, wherein the double bond can also be to        ring E,    -   C₃-C₈-alkinylene, which is optionally substituted once or twice        by methyl or hydroxy, as well as    -   C₁-C₈-alkylene, C₂-C₈-alkenylene or C₃-C₈-alkinylene, in which        one to three methylene units can be isosterically replaced by O,        S, NH, N(CH₃), N(COCH₃), N(SO₂CH₃), CO, SO or SO₂,    -   wherein the heterocyclic ring can optionally have a double bond        and-   n and-   p can be independent of each other 0, 1, 2 or 3, with the proviso    that n+p≦3,-   q is 2 or 3,-   R¹⁰ is selected from hydrogen, C₁-C₃-alkyl, hydroxy, hydroxymethyl    and-   R¹¹ is selected from hydrogen or an oxo group which is adjacent to    the nitrogen atom,-   G is hydrogen or    -   G1, G2, G3, G4 and G5, wherein-   G1 represents the residue    —(CH₂)_(r)—(CR¹³R¹⁴)_(s)—R¹²  (G1)    -   wherein-   r is 0, 1 or 2 and-   s is 0 or 1,-   R¹² is selected from hydrogen, C₁-C₆-alkyl, C₃-C₈-cycloalkyl, benzyl    or phenyl,    -   benzocyclobutyl, indanyl, indenyl, oxoindanyl, naphthyl,        dihydronaphthyl, tetrahydronaphthyl, oxotetrahydronaphthyl,        biphenylenyl, fluorenyl, oxofluorenyl, anthryl, dihydroanthryl,        oxodihydroanthryl, dioxodihydroanthryl, phenanthryl,        dihydrophenanthryl, oxodihydrophenanthryl, dibenzocycloheptenyl,        oxodibenzocycloheptenyl, dihydrodibenzocycloheptenyl,        oxodihydrodibenzocycloheptenyl, dihydrodibenzocyclooctenyl,        tetra-hydrodibenzocyclooctenyl and        oxotetrahydrodibenzocyclooctenyl, bound directly or over a        methylene group,    -   furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,        isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,        triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl,        triazinyl, imidazothiazolyl, benzofuryl, dihydrobenzofuryl,        benzothienyl, dihydrobenzothienyl, indolyl, indolinyl,        oxoindolinyl, dioxoindolinyl, benzoxazolyl, oxobenzoxazolinyl,        benzisoxazolyl, oxobenzisoxazolinyl, benzothiazolyl,        oxobenzthiazolinyl, benzoisothiazolyl, oxobenzoisothiazolinyl,        benzimidazolyl, oxobenzimidazolinyl, indazolyl, oxoindazolinyl,        benzofurazanyl, benzothiadiazolyl, benzotriazolyl,        oxazolopyridyl, oxodihydrooxazolopyridyl, thiazolopyridyl,        oxodihydrothiazolopyridyl, isothiazolopyridyl, imidazopyridyl,        oxodihydroimidazopyridyl, pyrazolopyridyl,        oxodihydropyrazolopyridyl, thienopyrimidinyl, chromanyl,        chromanonyl, benzopyranyl, chromonyl, quinolyl, isoquinolyl,        dihydroquinolyl, oxodihydroquinolinyl, tetrahydroquinolyl,        oxotetrahydroquinolinyl, benzodioxanyl, quinoxalinyl,        quinazolinyl, naphthyridinyl, carbazolyl, tetrahydrocarbazolyl,        oxotetrahydrocarbazolyl, pyridoindolyl, acridinyl,        oxodihydroacridinyl, pbenothiazinyl, dihydrodibenzoxepinyl,        oxodihydrodibenzoxepinyl, benzocycloheptathienyl,        oxobenzocycloheptathienyl, dihydrothienobenzo-thiepinyl,        oxodihydrothienobenzothiepinyl dihydrodibenzothiepinyl,        oxodihydrodibenzothiepinyl, octabydrodibenzothiepinyl,        dihydrodibenzazepinyl, oxodihydrodibenzazepinyl,        octahydrodibenzazepinyl, benzocycloheptapyridyl,        oxobenzocycloheptapyridyl, dihydropyrido-benzodiazepinyl,        dihydrodibenzoxazepinyl, dihydropyridobenzoxepinyl,        dihydropyridobenzoxazepinyl, oxodihydropyridobenzoxazepinyl,        dihydrodibenzothiazepinyl, oxodihydrodibenzothiazepinyl,        dihydropyridobenzothiazepinyl, oxodihydropyridobenzothiazepinyl,        bound directly or over a methylene group,-   R¹³ has the same meaning as R¹², but is selected independently    therefrom,-   R¹⁴ is selected from hydrogen, hydroxy, methyl, benzyl or phenyl,    -   indanyl, indenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl,        furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,        isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,        triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl,        triazinyl, benzofuryl, benzothienyl, indolyl, indolinyl,        benzoxazolyl, benzothiazolyl, benzimidazolyl, chromanyl,        quinolyl or tetrahydroquinolyl bound directly or over a        methylene group,-   G2 is selected from the residues    wherein the substituents R¹² and R¹⁴ can have the above meanings, or    represents the grouping    —NR¹²R¹⁴    over the nitrogen-bound ring atom of azetidine, pyrrolidine,    piperidine, (1H)tetrahydropyridine, hexahydroazepine,    (1H)tetrahydroazepine, octabydroazocine, pyrazolidine, piperazine,    hexyhydrodiazepine, morpholine, hexahydrooxazepine, thiomorpholine,    thiomorpholine-1,1-dioxide, 5-aza-bicyclo[2.1.1]hexane,    2-aza-bicyclo[2.2.1]heptane, 7-aza-bicyclo[2.2.1]heptane,    2,5-diaza-bicyclo[2.2.1]heptane, 2-aza-bicyclo[2.2.2]octane,    8-aza-bicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.2]octane,    9-azabicyclo[3.3.1]nonane, indoline, isoindoline,    (1H)-dihydroquinoline, (1H)-tetrahydroquinoline,    (2H)-tetrahydroisoquinoline, (1H)-tetrahydroquinoxaline,    (4H)-dihydrobenzoxazine, (4H)-dihydrobenzothiazine,    (1H)-tetrahydrobenzo[b]azepine, (1H)-tetrahydro-benzo[c]azepine,    (1H)-tetrahydrobenzo[d]azepine, (5H)-tetrahydrobenzo[b]oxazepine,    (5H)-tetrahydrobenzo[b]thiazepine,    1,2,3,4-tetrohydro-9H-pyrido[3,4-b]indole, (10H)-dihydroacridine,    1,2,3,4-tetrahydro-acridanone, (10H)-phenoxazine,    (10H)-phenothiazine, (5H)-dibenzazepine, (5H)-dihydrodibenzazepine,    (5H)-Octahydrodibenzazepine, (5H)-dihydrodibenzodiazepine,    (11H)-dihydrodibenzo[b,e]oxazepine,    (11H)-dihydrodibenzo[b,e]thiazepine,    (10H)-dihydrodibenzo[b,f]oxazepine,    (10H)-dihydrodibenzo[b,f]thiazepine or (5H)-tetrahydrodibenzazocine,-   G3 is the residue    —SO₂—(CH₂)_(r)R¹²  (G3),-   G4 is the residue    -   wherein-   Ar¹ and-   Ar² are selected independently of each other from phenyl, pyridyl or    naphthyl,-   G5 is the residue    —COR¹⁵  (G5)    -   wherein-   R¹⁵ is trifluoromethyl, C₁-C₆-alkoxy, C₃-C₆-alkenyloxy or benzyloxy    and aromatic ring systems in which the substituents can be    substituted independently of each other by one to three of the same    or different substituents from the series halogen, cyano,    C₁-C₆-alkyl, trifluoromethyl, C₃-C₈-Cycloalkyl, phenyl, benzyl,    hydroxy, C₁-C₆-alkoxy, C₁-C₆-alkoxy, which can be entirely or    partially substituted by fluorine, can carry benzyloxy, phenoxy,    mercapto, C₁-C₆-alkylthio, carboxy, C₁-C₆-alkoxycarbonyl,    benzyloxycarbonyl, nitro, amino, mono-C₁-C₆-alkylamino,    di-(C₁-C₆-alkyl)-amino, wherein two adjacent groups can form an    additional ring with a methylenedioxy bridge.

A further preferred embodiment of the invention is in compounds whichare distinguished in that the labelled substituents in formula (I)

have the following meaning:

-   R¹ is hydrogen, halogen, cyano, methyl, trifluoromethyl, hydroxy,    methoxy or methoxycarbonyl,-   R² is hydrogen or halogen,-   R³ is hydrogen,-   R⁴ is selected from hydrogen, C₁-C₃-alkyl or hydroxy,-   k is 0 or 1,-   A is selected from C₂-C₆-alkylene, which is optionally substituted    once or twice by hydroxy or fluorine, or    -   C₂-C₆-alkenylene, which is optionally substituted once or twice        by hydroxy or fluorine,    -   C₄-C₆-alkadienylene, which is optionally substituted by 1 or 2        fluorine atoms, or    -   1,3,5-hexatrienylene,-   D is C₂-C₈-alkylene, which is optionally substituted by methyl or    hydroxy,    -   C₂-C₈-alkenylene, which is optionally substituted by methyl or        hydroxy, wherein the double bond can also be to ring E, or    -   C₂-C₈-alkylene, C₂-C₈-alkenylene, wherein one to three methylene        units can be isosterically replaced by O, NH, N(CH₃), N(COCH₃),        N(SO₂CH₃) or CO,-   E is selected from the residues    -   wherein the heterocyclic ring can optionally have a double bond        and-   n and p can be, independent of each other, 0, 1, 2 or 3, with the    proviso that n+p≦3 and-   q is 2-   R¹⁰ is hydrogen, methyl or hydroxyl and-   R¹¹ is hydrogen or an oxo group adjacent to the nitrogen atom,-   G is selected from hydrogen, C₃-C₈-cycloalkyl, methoxycarbonyl,    tert-butoxycarbonyl, benzyloxycarbonyl, trifluoroacetyl,    diphenylphosphinoyl or the residues    -   wherein-   r is 0, 1 or 2 and-   s is 0 or 1,-   R¹² is hydrogen, methyl, benzyl or phenyl, indanyl, indenyl,    oxoindanyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl,    oxotetrahydronaphthyl, fluorenyl, oxofluorenyl, anthryl,    dihydroanthryl, oxodihydroanthryl, dioxodihydroanthryl,    dibenzocycloheptenyl, oxodibenzo-cyclohbeptnyl,    dihydrodibenzocycloheptenyl, oxodihydrodibenzocycloheptenyl bound    directly or over a methylene group,    -   furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,        isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,        triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl,        imidazothiazolyl, benzofuryl, dihydrobenzofuryl, benzothienyl,        dihydrobenzothienyl, indolyl, indolinyl, oxoindolinyl,        dioxoindolinyl, benzoxazolyl, oxobenzoxazolinyl, benzisoxazolyl,        oxobenzisoxazolinyl, benzothiazolyl, oxobenzthiazolinyl,        benzoisothiazolyl, oxobenzoisothiazotinyl, benzimidazolyl,        oxobenzimidazolinyl, benzofurazanyl, benzothiadiazolyl,        benzotriazolyl, oxazolopyridyl, oxodihydrooxazolopyridyl,        thiazolopyridyl, oxodihydrothiazolopyridyl, isothiazolopyridyl,        imidazopyridyl, oxodihydro-imidazopyridyl, pyrazolopyridyl,        thienopyrimidinyl, chromanyl, chromanonyl, benzopyranyl,        chromonyl, quinolyl, isoquinolyl, dihydroquinolyl,        oxodihydroquinolinyl, tetrahydroquinolyl,        oxotetrahydroquinolinyl, benzodioxanyl, quinoxalinyl,        quinazolinyl, naphthyndinyl, carbazolyl, tetrahydrocarbazolyl,        oxotetrahydrocarbazolyl, pyridoindolyl, acridinyl,        oxodihydroacridinyl, phenothiazinyl, dihydrodibenzoxepinyl,        benzocyclohepta-thienyl, oxobenzocycloheptathienyl,        dihydrothienobenzothiepinyl, oxodihydro-thienobenzothiepinyl        dihydrodibenzothiepinyl, oxodihydrodibenzothiepinyl,        dihydrodibenzazepinyl, oxodihydrodibenzazepinyl,        octahydrodibenzazepinyl, benzocycloheptapyridyl,        oxobenzocycloheptapyridyl, dibydropyridobenzoxepinyl,        dihydrodibenzothiazepinyl, oxodihydrodibenzothiazepinyl bound        directly or over a methylene group,-   R¹³ is hydrogen, methyl, benzyl or phenyl,-   R¹⁴ is selected from hydrogen, hydroxy, methyl, benzyl, phenyl,    -   naphthyl, furyl, thienyl, oxazolyl, thiazolyl, pyrazolyl,        imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, benzofuryl,        benzothienyl, indolyl, indolinyl, benzoxazolyl, benzothiazolyl,        benzimidazolyl, chromanyl, quinolyl or tetrahydroquinolyl, bound        directly or over a methylene group, wherein in formula (I)    -   —NR¹²R¹⁴ can also be selected from pyrrolidine, piperidine,        (1H)tetrahydropyridine, hexahydroazepine, Octahydroazocine,        piperazine, hexahydrodiazepine, morpholine, hexahydrooxazepine,        2-azabicyclo[2.2.1]heptane, 7-azabicyclo[2.2.1]heptane,        2,5-diazabicyclo[2.2.1]heptane, 8-azabicyclo[3.2.1]octane,        2,5-diazabicyclo[2.2.2]octane, indoline, isoindoline,        (1H)-dihydroquinoline, (1H)-tetrahydroquinoline,        (2H)-tetrahydroisoquinoline, (1H)-tetrahydroquinoxaline,        (4H)-dihydrobenzoxazine, (4H) dihydrobenzothiazine,        (1H)-tetrahydrobenzo[b]azepine, (1H)-tetrahydrobenzo[d]azepine,        (5H)-tetrahydrobenzo[b]oxazepine,        (5H)-tetrahydrobenzo[b]thiazepine,        1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol, (10H)-dihydroacridine,        1,2,3,4-tetrahydroacridanone, (5H)-dihydrodibenzazepine,        (5H)-dihydrodibenzodiazepine,        (11H)-dihydrodibenzo[b,e]oxazepine,        (11H)-dihydrodibenzo[b,e]thiazepine,        (10H)-dihydrodibenzo[b,f]oxaze-pine or        (5H)-tetrahydrodibenzazocine.

Compounds in which the labelled substituents in formula (I)

have the following meanings are very particularly preferred:

-   R¹ is hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl    or hydroxy,-   R² and-   R³ are hydrogen,-   R⁴ is hydrogen or hydroxy,-   k is 0 or 1,-   A is selected from C₂-C₄-alkylene, which is optionally substituted    by fluorine,-   D is selected from C₂-C₆-alkylene, C₂-C₆-alkenylene, wherein the    double bond can also be to ring E, and C₂-C₆-alkylene and    C₂-C₆-alkenylene, wherein a methylene unit can be isosterically    replaced by O, NH, N(CH₃) or CO or an ethylene group can be    isosterically replaced by NH—CO and/or CO—NH or a propylene group    can be isosterically replaced by NH—CO—O and/or O—CO—NH,-   E is selected from pyrrolidine, piperidine,    1,2,5,6-tetrahydropyridine, hexahydroazepine, morpholine and    hexahydro-1,4-oxazepine, wherein the heterocyclic ring optionally    adjacent to the nitrogen atom, can be substituted by an oxo group,-   G is selected from hydrogen, tert-butoxycarbonyl,    diphenylphosphinoyl, or one of the residues    wherein-   r is 0 or 1 and-   s is 0 or 1,-   R¹² is hydrogen, methyl, benzyl or phenyl,    -   indenyl, oxoindanyl, naphthyl, tetrahydronaphthyl, fluorenyl,        oxofluorenyl, anthryl, dihydroanthryl, oxodihydroanthryl,        dioxodihydroanthryl, dibenzocycloheptenyl,        dihydrodibenzocycloheptenyl bound directly or over a methylene        group,    -   furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl,        thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, imidazothiazolyl,        benzofuryl, benzothienyl, indolyl, oxoindolinyl, dioxoindolinyl,        benzoxazolyl, oxobenzoxazolinyl, benzothiazolyl,        oxobenzthiazolinyl, benzimidazolyl, oxobenzimidazolinyl,        benzofurazanyl, benzotriazolyl, oxazolopyridyl,        oxodihydrooxazolopyridyl, thiazolopyridyl,        oxodihydrothiazolopyridyl, chromanyl, chromanonyl, benzopyranyl,        chromonyl, quinolyl, isoquinolyl, oxodihydroquinolinyl,        tetrahydroquinolyl, oxotetrahydroquinolinyl, benzodioxanyl,        quinazolinyl, acridinyl, oxodihydroacridinyl, phenothiazinyl,        dihydrodibenzoxepinyl, benzocycloheptathienyl,        dihydrothienobenzothiepinyl, dihydrodibenzothiepinyl,        oxodihydrodibenzathiepinyl, dihydrodibenzazepinyl,        oxodihydrodibenzazepinyl, octahydrodibenzazepinyl,        benzocycloheptapyridyl, oxobenzocycloheptapyridyl,        dihydrodibenzothiazepinyl bound directly or over a methylene        group,-   R¹³ is hydrogen, methyl, benzyl or phenyl,-   R¹⁴ is hydrogen, hydroxy, methyl, benzyl or phenyl,    -   naphthyl, furyl, thienyl, pyridyl, benzofuryl, benzothienyl,        indolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl,        chromanyl, quinolyl or tetrahydroquinolyl bound directly or over        a methylene group, wherein in the formula    -   —NR¹²R¹⁴ can be selected from pyrrolidine, piperidine,        hexahydroazepine, morpholine, 2,5-diazabicyclo[2.2.1]heptane,        indoline, isoindoline, (1H)-dihydroquinoline,        (1H)-tetrahydroquinoline, (2H)-tetrahydroisoquinoline,        (1H)-tetrahydrobenzo[b]azepine, (1H)-tetrahydrobenzo[d]azepine,        (5H)-tetrahydro-benzo[b]oxazepine,        (5H)-tetrahydrobenzo[b]thiazepine, 1,2,3,4-tetrahydroacridanone,        (5H)-dihydrodibenzazepine, (11H)-dihydrodibenzo[b,e]-oxazepine        or (11H)-dihydrodibenzo[b,e]thiazepine and    -   wherein aromatic ring systems in the substituents can be        substituted, independently of each other, by one to three of the        same or different substituents from the series halogen, cyano,        C₁-C₆-alkyl, trifluoromethyl, C₃-C₈-cycloalkyl, phenyl, benzyl,        hydroxy, C₁-C₆-alkoxy, C₁-C₆-alkoxy, which can be entirely or        partially substituted by fluorine, can c benzyloxy, phenoxy,        mercapto, C₁-C₆-alkylthio, carboxy, C₁-C₆-alkoxycarbonyl,        benzyloxycarbonyl, nitro, amino, mono-C₁-C₆-alkylamino or        di-(C₁-C₆-alkyl)-amino, whereby two adjacent groups on the        aromatic ring or ring system can form an additional ring over a        methylenedioxy bridge.

Compounds are especially preferred which distinguish themselves in thatthe labelled substituents in formula (I)

have the following meanings:

-   R¹ is hydrogen, fluorine, methyl, trifluoromethyl or hydroxy,-   R² and-   R³ are hydrogen,-   R⁴ is hydrogen or hydroxy,-   k is 0,-   A is ethenylene (vinylene) or 1,3-butadienylene,-   D is selected from C₂-C₆-alkylene or C₂-C₆-alkenylene, wherein the    double bond can also be to ring E,-   E is selected from pyrrolidine, piperidine, hexahydroazepine or    morpholine,-   G is selected from benzyl, phenethyl, fluorenylmethyl,    anthrylmethyl, diphenylmethyl, fluorenyl or    dihydrodibenzocycloheptenyl,    -   furylmethyl, thienylmethyl, thiazolylmethyl, pyridylmethyl,        benzothienylmethyl, quinolylmethyl, phenyl-thienylmethyl,        phenyl-pyridylmethyl, dihydrodibenzoxepinyl,        dihydrodibenzothiepinyl,    -   acetyl, pivaloyl, phenylacetyl, diphenylacetyl,        diphenylpropionyl, naphthylacetyl, benzoyl, naphthoyl,        anthrylcarbonyl, oxofluorenylcarbonyl,        oxodihydro-anthrylcarbonyl or dioxodihydroanthrylcarbonyl,    -   furoyl, pyridylcarbonyl, chromonylcarbonyl, quinolylcarbonyl,    -   naphthylaminocarbonyl, dibenzylaminocarbonyl,        benzylphenylaminocarbonyl, diphenylaminocarbonyl,        indolinyl-1-carbonyl, dihydrodibenzazepin-N-carbonyl,        tetrahydroquinolinyl-N-carbonyl,        tetrahydrobenzo[b]azepinyl-N-carbonyl,    -   methanesulfonyl, phenylsulfonyl, p-toluenesulfonyl,        naphthylsulfonyl, quinolinsulfonyl and    -   diphenylphosphinoyl,    -   wherein aromatic ring systems can be substituted independently        of each other by one to three of the same or different        substituents from the series halogen, cyano, C₁-C₆-alkyl,        trifluoromethyl, C₃-C₈-cycloalkyl, phenyl, benzyl, hydroxy,        C₁-C₆-alkoxy, C₁-C₆-alkoxy, which can be entirely or partially        substituted by fluorine, benzyloxy, phenoxy, mercapto,        C₁-C₆-alkylthio, carboxy, C₁-C₆-alkoxycarbonyl,        benzyloxycarbonyl, nitro, amino, mono-C₁-C₆-alkylamino or        di-(C₁-C₆-alkyl)-amino, wherein two adjacent groups in the ring        or ring system can form an additional ring over a methylendioxy        bridge.

A series of exemplary compounds with the respective substituentdefinitions are listed in the following Table 1 for illustration of theinvention without restricting the scope of the compounds according tothe invention. TABLE 1 Exemplifying compounds of formula (I) accordingto the invention

Nr R¹ k A R⁴ D—E—G 1 H 0 CH═CH H

2 H 0 CH═CH—CH═CH H

3 H 0 CH═CH H

4 H 0 CH═CH H

5 H 0 CH═CH H

6 H 0 CH═CH H

7 H 0 CH═CH—CH═CH H

8 H 0 CH═CH(CH₂)₂ H

9 H 0 CH═CH H

10 H 0 CH═CH H

11 H 0 CH═CH H

12 H 0 CH═CH H

13 H 0 CH═CH H

14 H 0 CH═CH H

15 H 0 CH═CH—CH═CH H

16 H 0 CH═CH H

17 H 0 CH═CH H

18 H 0 CH═CH—CH═CH H

19 H 0 CH═CH—CH═CH H

20 H 0 CH═CH(CH₂)₂ H

21 H 0 CH═CH H

22 H 0

H

23 H 0 CH═CH H

24 H 0 CH═CH H

25 H 0 CH═CH H

26 H 0 CH═CH H

27 H 0 CH═CH H

28 H 0 CH═CH h

29 H 0 CH═CH H

30 H 0 CH═CH—CH═CH H

31 H 1 CH═CH H

32 H 0 CH═CH OH

33 H 0

H

34 H 0 C≡C H

35 H 0 CH═CH(CH₂)₂ H

36 H 0 CH═CH—CH═CH H

37 2-F 0 CH═CH—CH═CH H

38 H 0 (CH═CH)₃ H

39 H 0 CH═CH H

40 H 0 CH═CH H

41 H 0 CH═CH H

42 H 0 CH═CH H

43 H 0 CH═CH H

44 H 0 CH═CH H

45 H 0 CH═CH H

46 H 0 CH═CH—CH═CH H

47 H 0 CH═CH—CH═CH H

48 H 0 CH═CH—CH═CH H

49 H 0 CH═CH—CH═CH H

50 H 0 C≡C H

51 H 0 CH═CH H

52 H 0 CH═CH—CH═CH H

53 H 0 CH═CH H

54 H 0 CH═CH H

55 H 0 CH═CH—CH═CH H

56 H 1 CH═CH H

57 H 0 CH═CH(CH₂)₂ H

58 H 0 CH═CHCH₂CHF H

59 H 0 CH═CH H

60 H 0 CH═CH H

61 H 0 CH═CH—CH═CH H

62 H 0 CH═CH H

63 H 1 CH═CH H

64 H 0 CH═CH OH

65 H 0

H

66 H 0 C≡C H

67 H 0 CH═CH(CH₂)₂ H

68 H 0

H

69 H 0 (CH₂)₂CH═CH H

70 H 0 CH═CH—CH═CH H

71 H 0 CH═CH—CH═CH CH₃

72 2-F 0 CH═CH—CH═CH H

73 2-F 0 CH═CH—CH═CH OH

74 4-F 0 CH═CH—CH═CH H

75 5-F 0 CH═CH—CH═CH H

76 6-F 0 CH═CH—CH═CH H

77 2-Cl 0 CH═CH—CH═CH H

78 6-CH₃ 0 CH═CH—CH═CH H

79 2-OH 0 CH═CH—CH═CH H

80 H 0 (CH═CH)₃ H

81 H 0 CH═CH H

82 2-F 0 CH═CH H

83 5-F 0 CH═CH H

84 6-CH₃O 0 CH═CH H

85 H 0 CH═CH—CH═CH H

86 H 0 CH═CH H

87 H 0 CH═CH—CH═CH H

88 H 0 CH═CH H

89 H 0 CH═CH H

90 H 0 CH═CH H

91 H 0 CH═CH H

92 H 0 CH═CH H

93 H 0 CH═CH—CH═CH H

94 H 0 CH═CH H

95 H 0 CH═CH—CH═CH H

96 H 0 CH═CH H

97 H 0 CH═CH H

98 H 0 CH═CH—CH═CH H

99 H 0 CH═CH H

100 H 0 CH═CH H

101 H 0 CH═CH H

102 H 0 CH═CH H

103 H 0 CH═CH H

104 H 0 CH═CH H

105 H 0 CH═CH H

106 H 0 CH═CH H

107 H 0 CH═CH H

108 H 0 CH═CH H

109 H 0 CH═CH—CH═CH H

110 H 0 C≡C H

111 H 0 CH═CH—CH═CH H

112 H 0 C≡C H

113 H 0 (CH₂)₂CH═CH H

114 H 0 CH═CH—CH═CH H

115 H 0 CH═CH—CH═CH H

116 H 0 CH═CH—CH═CH H

117 H 0 CH═CH—CH═CH H

118 H 0 CH═CH—CH═CH H

119 H 0 CH═CH H

120 H 0 CH═CH—CH═CH H

121 H 0 CH═CH H

122 H 0 CH═CH—CH═CH H

123 H 0 CH═CH H

124 H 0 CH═CH—CH═CH H

125 H 0

H

126 H 0 CH═CH—CH═CH H

127 H 0 CH═CHCH₂CHF H

128 H 0 CH═CH—CH═CH H

129 H 0 C≡C H

130 H 0 CH═CH H

131 H 0 CH═CH—CH═CH H

132 H 0 CH═CH H

133 H 0 CH═CH H

134 H 0 CH═CH H

135 H 0 CH═CH—CH═CH H

136 H 0 CH═CH H

137 H 0 CH═CH—CH═CH H

138 H 0 CH═CH H

139 H 0 CH═CH—CH═CH H

140 H 0 CH═CH H

141 H 0 CH═CH—CH═CH H

142 H 0 CH═CH H

143 H 0 CH═CH H

144 H 0 CH═CH H

145 H 0 CH═CH—CH═CH H

146 H 0 CH═CH H

147 H 0 CH═CH H

148 H 0 CH═CH—CH═CH H

149 H 0 CH═CH(CH₂)₂ H

150 H 0 CH═CH H

151 H 0 CH═CH—CH═CH H

152 H 0 CH═CH H

153 H 0 CH═CH H

154 H 0 CH═CH—CH═CH H

155 H 0 CH═CH H

156 H 0 CH═CH H

157 H 0 CH═CH—CH═CH H

158 H 0 CH═CH H

159 H 0 CH═CH H

160 H 0

H

161 H 0

H

162 H 0 CH═CH—CH═CH H

163 H 0 CH═CH H

164 H 0 CH═CH CH₃

165 H 0 CH═CH H

166 H 0 CH═CH H

167 H 0 CH═CH H

168 H 0 CH═CH—CH═CH H

169 H 0 CH═CH H

170 H 0 (CH₂)₂CH═CH H

171 H 0 CH═CH H

172 2-F 0 CH═CH H

173 H 0 CH═CH—CH═CH H

174 H 0 CH═CH H

175 H 0 CH═CH H

176 H 0 CH═CH—CH═CH H

177 H 0 CH═CH H

178 H 0 CH═CH H

179 H 0 CH═CH—CH═CH H

180 H 0 CH═CH H

181 H 0 CH═CH H

182 4-F 0 CH═CH H

183 H 0 CH═CH—CH═CH H

184 H 0 CH═CH H

185 H 0 CH═CH H

186 H 0 (CH═CH)₃ H

187 H 0 CH═CH H

188 H 0 CH═CH—CH═CH H

189 H 0 CH═CH H

190 H 0 C≡C H

191 H 0 CH═CH H

192 H 0 CH═CH H

193 H 0 CH═CH H

194 H 0 CH═CH—CH═CH H

195 H 0 CH═CH H

196 2-Cl 0 CH═CH H

197 H 0 CH═CH H

198 H 0 CH═CH H

199 H 0 CH═CH H

200 H 0 CH═CH—CH═CH H

201 H 0 CH═CH H

202 H 0 CH═CH—CH═CH H

203 H 0 CH═CH H

204 H 0 CH═CH—CH═CH H

205 H 0 CH═CH H

206 H 0 CH═CH—CH═CH H

207 H 0 CH═CH H

208 H 0 CH═CH H

209 H 0 CH═CH—CH═CH H

210 H 0 CH═CH H

211 H 0 CH═CH H

212 H 0 CH═CH H

213 H 0 CH═CH H

214 H 0 CH═CH—CH═CH H

215 H 0 CH═CH H

216 H 0 CH═CH H

217 H 0 CH═CH H

218 H 0 CH═CH—CH═CH H

219 H 0 CH═CH H

220 H 0 C≡C H

221 H 0 (CH₂)₂CH═CH H

222 H 0 CH═CH—CH═CH H

223 H 0 CH═CH H

224 H 0 CH═CH H

225 H 0 CH═CH H

226 H 0 CH═CH—CH═CH H

227 H 0 CH═CH H

228 H 0 CH═CH H

229 H 0 CH═CH H

230 H 0 CH═CH—CH═CH H

231 H 0 CH═CH H

232 H 0 CH═CH H

233 H 0 CH═CH—CH═CH H

234 H 0 CH═CH H

235 H 0 CH═CH H

236 H 0 CH═CH—CH═CH H

237 H 0 CH═CH H

238 H 0 CH═CH—CH═CH H

239 H 0 CH═CH H

240 H 0 CH═CH H

241 H 0 CH═CH—CH═CH H

242 H 0 CH═CH H

243 H 0 CH═CH—CH═CH H

244 H 0 C≡C H

245 H 0 (CH═CH)₃ H

246 H 0 CH═CH H

247 H 0 CH═CH H

248 H 0 CH═CH H

249 H 0 CH═CH H

250 H 0 CH═CH H

251 H 0 CH═CH—CH═CH H

252 H 0 CH═CH H

253 H 0 CH═CH H

254 H 0 CH═CH H

255 H 0 CH═CH—CH═CH H

256 H 0 CH═CH H

257 H 0 CH═CH—CH═CH H

258 H 0 CH═CH H

259 H 0 CH═CH H

260 H 0 CH═CH H

261 H 0 CH═CH—CH═CH H

262 H 0 C≡C H

263 H 0 CH═CH H

264 H 0 CH═CH H

265 H 0 CH═CH H

266 H 0 CH═CH H

267 H 0 CH═CH H

268 H 0 CH═CH—CH═CH H

Synthesis Methods

Further subject-matter of the invention are analogous methods for theproduction of the compounds of formula (I) according to the invention.

Method (A):

Compounds of formula (I) are(a) obtained by reacting carboxylic acids of formula (II)

-   -   in which R¹, R², R³, A and k have the meaning described above or        their reactive derivatives are reacted with compounds of formula        (III)    -   wherein D, E, G and R⁴ also have the above described meanings.

Reactive derivatives of compound (II) can be, for example, activatedesters, anhydrides, acid halides (especially acid chlorides) or simplelow alkyl esters. Suitable acitivated esters are, for example,p-nitrophenyl ester, 2,4,6-trichlorphenyl ester, pentachlorophenylester, cyanomethyl ester, esters of N-hydroxysuccinimide, ofN-hydroxyphthalimides, of 1-hydroxybenzotriazol, of N-hydroxypiperidine,of 2-hydroxypyridine or of 2-mercaptopyridine, etc. Anhydrides can besymmetric anhydrides or mixed, as they are obtained, for example, withpivaloyl chloride or with chloroformates. Aromatic (for examplechloroformic phenyl ester), araliphatic (for example chloroformic benzylester) or aliphatic chloroformates (for example chloroformic methylester, -ethyl ester or -isobutyl ester) can be used for this.

Reaction of compounds (II) with compounds (III) can also be carried outin the presence of condensation agents such as dicyclobexylcarbodiimide,1-ethyl-3-(3-di-methylaminopropyl)carbodiimide hydrochloride,N,N′-carbonyldiimidazol, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline,etc. If carbodiimides are used as the condensation agent, reagents suchas N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazol,N-hydroxypiperidine, etc. can be advantageously added.

Compounds of formula (III) can be used for reaction as free bases aswell as in the form of their acid addition salts. For this, the salts ofinorganic acids are to be preferred, i.e. hydrochlorides, hydrobromidesor sulfates.

Reaction of compounds (II) or their reactive derivatives with compounds(III) are normally carried out in a suitable, preferably inert solvent.As examples, aromatic hydrocarbons such as benzene, toluene, xylene,halogenated hydrocarbons (for example dichloromethane, chloroform,1,2-dichloroethane, trichloroethylene), ether (for example diethylether, tetrahydrofuran, dioxane, glycol dimethyl ether), ethyl acetate,acetonitrile or polar aprotic solvents such as, for example,dimethylsulfoxide, dimethylformamide or N-methylpyrrolidone are to benamed. Pure solvents, as well as mixtures of two or more, can be used.

The reaction is optionally carried out in the presence of an auxiliarybase. Suitable examples for this are alkali metal carbonates (sodiumcarbonate, potassium carbonate), alkali metal hydrogen carbonates(sodium hydrogen carbonate, potassium hydrogen carbonate), or organicbases such as, for example, triethylamine, ethyl diisopropylamine,tributylamine, N-methylmorpholine or pyridine. A suitable excess ofcompound (III) can also be used as a base. If compounds (III) are usedin form of their acid addition salts, then it is appropriate to considerthe amount of auxiliary base used as equivalent.

The reaction temperatures can—depending on reactivity of the educts—varyin a wide range. Generally, the reaction is carried out at temperaturesbetween −40° C. and 180° C., preferably between −10° C. and 130° C.,especially at the boiling point of the solvent used.

The starting compounds (II) and (III) are known and/or can be producedaccording to known methods in an analogous manner. Moreover, theproduction of representative examples is further described below.

Compounds of formula (I) can be

(b) produced by reaction of compounds of formula (I), wherein G ishydrogen, and which themselves also have the activities found accordingto the invention, with a compound of formula (IV),L-G  (IV)in which G has the meaning given above, with the exception of hydrogen,and L represents a suitable nucleofuge or reactive group. The type ofnucleofuge or reactive group L and the conditions of the reaction aredependent of the nature of group G.

Compounds of formula (I), in which G, with the exception of hydrogen,has the meaning of (G1) according to the above definition can, asidefrom method (a), also be

(c) produced by reacting compounds of formula (I), in which G ishydrogen, with a suitable alkylation agent and/or arylation agent offormula (IV), wherein G is an alkyl-, alkenyl-, alkinyl-, cycloalkyl-,aryl-, aralkyl-, heteroaryl- or heteroaralkyl residue and the leavinggroup L can represent a reactive derivative of an alkohol for example, ahalogen atom such as chlorine, bromine or iodine or a sulfonic acidester, i.e. for example a methanesulfonyloxy-,trifluoromethanesulfonyloxy-, ethanesulfonyloxy-, benzenesulfonyloxy-,p-toluenesulfonyloxy-, p-bromobenzenesulfonyloxy- orm-nitro-benzenesulfonyloxy residue, etc. or a reactive group L can alsobe an epoxide group, wherein the reaction occurs under addition.

The reaction of compounds (I), in which G is a hydrogen, and (IV) isusually conducted in a suitably inert solvent. As solvents of this type,aromatic hydrocarbons (benzene, toluene, xylene), ethers (for exampletetrahydrofuran, dioxane, glycol dimethyl ether), ethyl acetate,acetonitrile, ketones (acetone, ethyl methyl ketone), polar proticsolvents such as alcohols (ethanol, isopropanol, butanol, glycolmonomethyl ether) or polar aprotic solvents such as, for example,dimethylsulfoxide, dimethylformamide or N-methylpyrrolidone can beconsidered. Pure solvents as well as mixtures of two or more can also beused. Preferably, the reactions are carried out in the presence ofbases, whereby said bases can be used as in method (a) above. Ifchlorides or bromides are used as compound (IV), the reaction can beaccelerated by the addition of alkali metal iodides (sodium iodide,potassium iodide). The reaction temperatures can vary between 0° C. and180° C. depending on the reactivity of the educts, but preferably liebetween 20° C. and 130° C.

Compounds of formula (I), in which G represents an acyl residue, acarbamoyl residue, a sulfonyl residue or a phosphinoyl residue accordingto the above definition, can also be produced, aside from the abovemethod (a),

(d) by reacting compounds of formula (I), wherein G is hydrogen, with acarboxylic acid, carbamic acid, sulfonic acid and/or phosphinic acid offormula (V),HO-G  (V)wherein G is an acyl residue, carbamoyl residue, sulfonyl residue orphosphinoyl residue according to definition, or their derivativescapable of reaction. Preferred derivatives of carboxylic acids and/orsulfonic acids (V) which are capable of reaction are symmetric orunsymmetric carboxylic acid anhydrides and/or sulfonic acid anhydridesor acyl- and/or sulfonyl halides, especially acyl- and/or sulfonylchlorides. Preferably, derivatives of carbamates and/or phosphinic acidswhich are capable of reaction are the carbamoyl halides and/orphosphinyl halides, especially carbamyl- and/or phosphinyl chlorides.The reaction of the acids (V) and/or their reactive derivatives withcompounds (I), in which G is hydrogen, preferably occurs in the presenceof auxiliary bases in solvents and under conditions as they aredescribed in method (a).

Compounds of formula (I), wherein G represents a carbamoyl residueaccording to the definition (G2b) with the proviso that r=0, thegrouping is

can also be produced, aside from the methods (a) and (d)(e) by reacting compounds of formula (I), in which G is hydrogen with acarbonyl group transmitter to an intermediate product and subsequentlyreacting this directly with a primary or secondary amine with theformula (VI)H—NR¹²R¹⁴  (VI)wherein R¹² and R¹⁴ and/or the grouping —NR¹²R¹⁴ have the meaningsaccording to the above definitions without having to purify or isolatethe intermediate product.

Bis-trichloromethyl carbonate (triphosgene) and carbonyldiimidazol havebeen proven as particularly reactive carbonyl group transmitters. Thereaction of compounds of formula (I), wherein G is hydrogen, withtriphosgene and/or carbonyldiimidazol are typically conducted in anabsolute, inert solvent in the presence of a tertiary organic amine asan auxiliary base in such a manner that the solution of compounds (I)and the auxiliary base are slowly poured into a solution of anequivalent amount of carbonyl group transmitter. Thereby, the reactionrequires molar ratios of 1:1 for the reaction of compound (I) andcarbonyldiimidazol, and, in contrast, a ratio of 1:0.35 for the use oftriphosgene. After complete reaction of the components to theintermediate product, compound (VI) is added in stochiometric amounts orin excess as a solution or a solid and the reaction is typicallycompleted at elevated temperature. Suitable inert solvents are, forexample hydrocarbons such as hexane, heptane, benzene, toluene, xylene,chlorinated hydrocarbons (for example dichloromethane, chloroform,1,2-dichloroethane, trichloroethylene), ethers (for example diethylether, tetrahydrofuran, dioxane), esters such as ethyl acetate, butylacetate, acetonitrile or polar aprodic solvents such as formamide ordimethylformamide. Pure solvents as well as mixtures can be useddiversely. Sometimes it is of advantage to carry out the first partialreaction at low temperature in a low-viscosity, highly-volatile solventand to remove the solvent after formation of the intermediate andreplace it by a higher boiling solvent.

Amines such as for example triethylamine, ethyl diisopropylamine,tributylamine, N-methylmorpholine or pyridine are suitable as auxiliarybases. If compounds (I) or (VI) are used as salts, the amount of theauxiliary base is increased accordingly. The reaction temperatures canlie in between −40° C. and 50° C. for the first partial reaction,preferably at 0° C. to 30° C., and between 0° C. and 150° C. for thesecond partial reaction, preferably at 20° C. to 120° C.

Compounds of formula (I), wherein G represents a carbamoyl residueaccording to the definition (G2b) with the proviso that r=0 andR¹⁴=hydrogen, the grouping is

can also be produced, aside from methods (a), (d) and (e)(f) by reacting the compounds of formula (I) in which G is hydrogen,with an isocyanate of formula (VII) in which R¹² has the meaningaccording to the above definitionO═C═N—R¹²  (VII).

Reaction of the compounds of formula (I), in which G is hydrogen, withthe isocyanates of formula (VII) are conducted thereby in an absolute,inert solvent which can be a hydrocarbon such as pentane, hexane,heptane, benzene, toluene, or xylene, chlorinated hydrocarbons (such asdichloromethane, chloroform, 1,2-dichloroethane, trichloroethylene),ethers (for example, diethyl ether, tetrahydrofuran, dioxane), esterssuch as ethyl acetate, butyl acetate, or polar aprotic solvents such asformamide or dimethylformamide. mixtures of various solvents can also beused. Thereby, the reaction temperatures can vary in the region from−20° C. to 150° C., but preferably lie at 20° C. to 100° C.

As already mentioned, the compounds of formula (I), wherein G ishydrogen, are themselves compounds with tumor growth inhibiting activityand/or cytostatic and immunosuppressive effectiveness. However,independent of their therapeutic applicability, they also representuseful intermediate compounds for the production of a multitude of othercompounds according to the invention corresponding to (c) to (f).

They themselves can, in principle, be produced according to method A byreacting a carboxylic acid of formula (II) with amines of formula (III)in which G is hydrogen as described above. However, since the compoundsof formula (III) with hydrogen as G represent α,ω-diamines, theformation of product mixtures is always to be expected in their reactionwith carboxylic acids (II) or their reactive derivatives making asubsequent separation necessary.

In contrast, compounds of formula (I), in which G is hydrogen, areessentially more advantageously produced from other compounds of formula(I), in which G is a selectively cleavable group under mild conditions,i.e. corresponds to a nitrogen protective group.

Among the compounds according to formula (I) with tumor growthinhibiting and/or cytostatic or immunomodulatory and/orimmunosuppressive properties, are compounds in which G represents a4-methoxybenzyl group, a triphenylmethyl group, a methoxy- and/orethoxycarbonyl group, a tert-butoxycarbonyl group, an allyloxycarbonylgroup or a trifluoroacetyl group. Thus, compounds of formula (I) with a4-methoxybenzyl group as G are transformed into compounds of formula (I)with hydrogen as & by selective oxidation with ammonium-cer(IV)-nitratefor example. The cleavage of simple alkoxycarbonyl groups such as themethoxy- or ethoxycarbonyl group as well as the trifluoroacetyl group asG in compounds of formula (I) succeed by alkali hydrolysis under mildconditions without cleaving the A and D linked amide function. This issuitably valid for the cleavage of the triphenylmethyl group and thetert-butoxycarbonyl group as G in compounds of formula (I), which occursin acidic medium under mild conditions. Finally, compounds of formula(I) with an allyloxycarbonyl group as G can be converted into such withhydrogen as G in neutral medium with palladium catalyst. All thesemethods are fully familiar to the person skilled in the art, and arefurthermore also documented in monographs (see for example Greene, Wuts,Protective Groups in Organic Synthesis, New York, 1991).

Compounds of formula (I), wherein R⁴ is an alkyl, alkenyl, alkinyl orcycloalkyl residue according to the above definition can also beproduced, aside from the methods (a) and (b),

(g) by reacting compounds of formula (I), wherein R⁴ is hydrogen, with asuitable alkylation agent of formula (VIII)L-R⁴  (III)wherein R⁴ is an alkyl, alkenyl, alkinyl or cycloalkyl residue accordingto the above definition and L is a suitable nucleofuge, i.e. for examplea halogen atom such as chlorine, bromine or iodine or a sulfonic acidester of an alcohol. Preferred sulfonic acid esters (VIII) contain amethylsulfonyloxy residue, trifluoromethanesulfonyloxy-,p-toluenesulfonyloxy-, p-bromobenzenesulfonyloxy- orm-nitrobenzenesulfonyloxy residue as L.

As an amide alkylation in the presence of tertiary amino groups, thisreaction requires the use of strong auxiliary bases such aspotassium-tert-butylate, sodium hydride, potassium hydride or butyllithium in aprotic, inert solvents. Such solvents can be for examplealiphatic or aromatic hydrocarbons (pentane, hexane, heptane, benzene,toluene), ethers (for example, tetrahydrofuran, dioxane) or polarsolvents such as dimethylsulfoxide, dimethylformamide orN-methylpyrrolidone. Depending on the reactivity of the educts, thereaction temperatures can lie between 40° C. and 140° C. preferablybetween −20° C. and 80° C.

The compounds of formula (I) produced according to the methods (a) to(g) can be isolated and purified in a known manner, for example bysubjecting the residue after distillation of the solvent to partition,extraction, re-precipitation or re-crystallization or anotherpurification method. For this, column chromatography on a suitablesupport or preparative, middle or high pressure liquid chromatographyare preferred for this.

The compounds (I) awe first normally obtained in form of their freebases or their hydrates or solvates, depending on the type of isolationand purification. Their addition salts with pharmaceutically suitableacids are obtained in a typical manner by converting the base with thedesired acid in a suitable solvent. Depending on the number of basiccenters of compound (I), one or more equivalent acids per mole of basecan be bound.

Suitable solvents are, for example, chlorinated hydrocarbons such asdichloromethane or chloroform; ethers such as diethyl ether, dioxane ortetrahydrofuran; acetonitrile; ketones such as acetone or ethyl methylketone; esters such as methyl acetate or ethyl acetate or low molecularalcohols such as methanol, ethanol or isopropanol; and water. Puresolvents as well as mixtures of two or three solvents can also be used.The salts can be isolated by crystallization, precipitation or theevaporation of the solvent. Thereby, they optionally accumulate ashydrates or solvates.

The bases can be recovered from the salts by alkalization, for examplewith aqueous ammonia solution, alkali carbonate or diluted sodiumhydroxide solution.

The following listed compounds and/or their pharmaceutically acceptablesalts, if not already concretely labelled as such, are particularlypreferred.

-   N-[4-(1-methylsulfonylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide,-   N-{4-[1-(2-naphthylsulfonyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide,-   N-{4-[1-(2-naphthylsulfonyl)-piperidin-4-yl]-butyl}-5-(pyridin-3-yl)-2,4-pentadienoic    acid amide,-   N-{4-[1-(1-naphthylaminocarbonyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide,-   N-[4-(1-diphenylaminocarbonyl-piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide,-   N-[4-(1-diphenylaminocarbonyl-piperidin-4-yl)-butyl]-5-(pyridin-3-yl)-2,4-pentadienoic    acid amide,-   N-{4-[1-(10,11-dihydrodibenzo[b,f]azepin-5-yl-carbonyl)-piperidin    4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide,-   N-[4-(1-diphenylphosphinoyl-piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide,-   N-[4-(1-acetylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide,-   N-[4-(1-diphenylacetyl-piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide,-   N-{4-[1-(3,3-diphenylpropionyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-actylamide,-   N-[4-(1-benzoylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide,-   N-[4-(1-benzoylpiperidin-4-yl)-butyl]-5-(pyridin-3-yl)-2,4-pentadienoic    acid amide,-   N-{4-[1-(9-oxo-9H-fluoro-4-yl-carbonyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide,-   N-{4-[1-(phenylpyridin-3-yl-methyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide,-   N-{4-[1-(phenylpyridin-4-yl-methyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide,-   N-{4-[1-(6,11-dihydrodibenzo[b,e]oxepin-11-yl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide,-   N-{4-[1-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide,-   N-[7-(1-diphenylmethylpiperidin-4-yl)-heptyl]-3-(pyridin-3-yl)-acrylamide,-   N-[8-(1-diphenylmethylpiperidin-4-yl)-octy]-3-(pyridin-3-yl)-acrylamide,-   N-[3-(1-diphenylmethylpiperidin-4-yloxy)-propyl]-3-(pyridin-3-yl)-acrylamide,-   N-[3-(1-benzylpiperidin-4-yloxy)-propyl]-3-(pyridin-3-yl)-acrylamide,-   N-[2-(1-diphenylmethylpiperidin-4-yl)-ethyl]-5-(pyridin-3-yl)-2,4-pentadienoic    acid amide,-   N-[4-(1-diphenylmethylpiperidin-4-yl)butyl]-5-(pyridin-3-yl)-2,4-pentadienoic    acid amide,-   N-[5-(1-diphenylmethylpiperidin-4-yl)-pentyl]-5-(pyridin-3-yl)-2,4-pentadienoic    acid amide or-   N-[6-(1-diphenylmethylpiperidin-4-yl)-hexyl]-5-(pyridin-3-yl)-2,4-pentadienoic    acid amide.

SYNTHETIC EXAMPLES For the End Products of the Invention According toFormula (I)

In the following production examples for the end products, theabbreviations stand for the following terms:

MP=melting point,

RT=room temperature,

THF=tetrahydrofuran,

DMF=dimethylformamide,

CDI=carbonyldiimidazol,

abs.=absolute,

EDC=N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride,

HOBT=1-hydroxybenzotriazol,

TEA=triethylamine,

¹H-NMR-Spectrum=proton resonance spectrum, taken at 100 MHz. Thechemical shifts are given in ppm against TMS as a standard (δ=0.0),whereby

s=singlet,

d=doublet,

t=triplet,

dt=doublet-triplet,

m=multiplet,

ar=aromatic,

py=pyridine.

Example 1N-{4-[1-(diphenylaminocarbonyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)acrylamide (substance 199)

6.5 g (18.0 mmol)N-[4-(piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide dihydrochloride(K22.142) and 5.77 ml (41.4 mmol) TEA are placed in 70 ml abs.dichlormethane and cooled to ca. 0° C. under moisture exclusion. 4.58 g(19.8 mmol) N,N-diphenylcarbamic acid chloride are dissolved in 20 mlabs. dichlormethane and added dropwise. The mixture is stirred at RTovernight without further cooling. 4 ml (28.7 mmol) TEA are added andthe red colored suspension is stirred a further 2 hours at RT.Subsequently, the batch is washed with 80 ml water. The organic phase isdried over sodium sulfate and the solvent is removed under vacuum. Theresidue is chromatographically purified over silica gel with CHCl₃/CH₃OH(98/2) and crystallized twice, each from 60 ml acetic acid ethyl ester,after drawing off the solvent. Beige colored crystals with a MP of132-134° C.: yield: 5.3 g (60%). C₃₀H₃₄N₄O₂ (482.6) IR-spectrum (KBr):ν(NH) 3300cm⁻¹ ν(C═O) 1660cm⁻¹ ¹H-NMR-spectrum (CDCl₃): 0.60-1.75(11H,m, piperidine, piperidine-(CH₂)₃) 2.40-2.85(2H, m, piperidine) 3.33(2H,dt, CONHCH ₂. J=6.5Hz. J=12.7Hz) 3.85-4.20(2H, m, piperidine)5.95-6.20(1H, m, NH) 6.42(1H, d, CH═CHCO, J=15.7Hz) 6.90-7.45(11H, m,ar, py) 7.59(1H, d, CH═CHCO, J=15.7Hz) 7.65-7.90(1H, m, py)8.45-8.60(1H, m, py) 8.65-8.85(1H, m, py)

Example 2N-[4-(1-diphenylacetyl-piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide(substance 150)

Production occurs analogously to example 1. However, no TEA issubsequently added.

Batch size: 5.0 g (13.9 mmol)N-[4-(piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide dihydrochloride(substance 14 as a dihydrochloride), 5.8 ml (41.6 mmol) TEA and 3.9 g(15.2 mmol) diphenylacetic acid chloride,

In the purification, this is washed twice, each with 50 ml water. Thechromatographic purification is carried out with CHCl₃/CH₃OH (97/3 to95/5). The residue is first crystallized twice, each from 15 ml aceticacid ethyl ester and then from 18 ml ethanol/diethyl ether (5/1).Colorless crystals remain with a MP of 161° C.; yield: 3.6 g (53%).C₃₁H₃₅N₃O₂ (481.6) IR-spectrum (KBr): ν(NH) 3280cm⁻¹ ν(C═O) 1665,1530cm⁻¹ ν(C═C) 1615cm⁻¹ ¹H-NMR-spectrum (CDCl₃): 0.50-1.85(11H, m,piperidine, piperidine-(CH₂)₃) 2.40-3.10(2H, m, piperidine) 3.32(2H, dt,CONHCH ₂. J=6.5Hz. J=12.6Hz) 3.80-4.05(1H, m, piperidine) 4.55-4.80(1H,m, piperidine) 5.23(1H, Ar₂CH) 6.10-6.35(1H, m, NH) 6.44(1H, d, CH═CHCO,J=15.7Hz) 7.10-7.45(11H, m, ar, py) 7.59(1H, d, CH═CHCO, J=15.7Hz)7.60-7.85(1H, m, py) 8.50-8.65(1H, m, py) 8.65-8.80(1H, m, py)

Example 3N-{4-[1-(2-naphthyl-sulfonyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide(substance 219)

Production occurs analogously to example 2.

Batch size: 6.0 g (16.6 mmol)N-[4-(piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide dihydrochloride(substance 14 as dihydrochloride), 5.6 ml (40.0 mmol) TEA and 2.5 g(11.0 mmol) naphthalin-2-sulfonic acid chloride in 70 ml abs.dichlormethane.

In the work up, this is washed twice, each with 70 ml water. Thechromatographic purification is carried out with CHCl₃₁CH₃OH (95/5 to94/6). The residue is crystallized from 30 ml acetic acid ethyl ester.Repeated chromatographic purification with CHCl₃/CH₃OH (9515). Yield:2.7 g (57%); amorphic solid with a MP of 85-87° C. C₂₇H₃₁N₃O₃S (477.5)IR-spectrum (KBr): ν(NH) 3320cm⁻¹ ν(C═O) 1690, 1560cm⁻¹ ν(C═C) 1640cm⁻¹¹H-NMR-spectrum (CDCl₃): 0.90-1.95(11H, m, piperidine,piperidine-(CH₂)₃) 2.10-2.50(2H, m, piperidine) 3.34(2H, dt, CONHCH ₂.J=6.5Hz, J=12.5Hz) 3.65-4.00(2H, m, piperidine) 5.85-6.15(1H, m, NH)6.46(1H, d, CH═CHCO, J=15.7Hz) 7.15-8.10(9H, m, ar, py. CH═CHCO)8.33(1H, s, Ar) 8.50-8.65(1H, m, py) 8.65-8.80(1H, m, py)

Example 4N-{4-[1-(1-naphthylaminocarbonyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)acrylamide (substance 195)

2.35 g (13.9 mmol) 1-naphthyl isocyanate are dissolved in 10 ml abs. THFand a solution of 4.0 g (13.9 mmol)N-[4-(piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide (substance 14)in 30 ml abs. THF is added dropwise at RT under moisture exclusion. Amerca. one hour, a white precipitate forms and the suspension is stirred atRT overnight. The solid is drawn off, chromatographically purified oversilica gel with CHCl₃/CH₃OH (95/5 to 93/7) and crystallized fromisopropanol after removal of the solvent. Colorless crystals remain witha MP of 198-200° C.; yield: 2.2 g (34%). C₂₈H₃₂N₄O₂ (456.6) IR-spectrum(KBr): ν(NH) 3240cm⁻¹ ν(C═O) 1660, 1560cm⁻¹ ν(C═C) 1615cm⁻¹¹H-NMR-spectrum (CDCl₃): 1.00-1.95(11H, m, piperidine,piperidine-(CH₂)₃) 2.75-3.15(2H, m, piperidine) 3.37(2H, dt, CONHCH ₂.J=6.5Hz. J=12.7Hz) 3.95-4.25(2H, m, piperidine) 5.75-6.05(1H, m, NH)6.42(1H, d, CH═CHCO, J=15.6Hz) 6.70(1H, s, NH) 7.20-8.00(10H, m, ar, py.CH═CHCO) 8.50-8.65(1H, m, py) 8.65-8.80(1H, m, py)

Example 5N-{4-[1-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide(substance 136)

7.02 g (21.5 mmol)N-[4-(piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide dihydrochloride(substance 14 as a dihydrochloride) are suspended in 100 ml abs.dichlormethane and added to 7.08 g (70.0 mmol) TEA. The mixture iscooled to ca. 0° C. under moisture exclusion and a solution of 5.30 g(21.5 mmol) 11-chlor-6,11-dihydro-dibenzo[b,e]thiepine in 10 ml abs.dichlormethane is added dropwise. The mixture is stirred for 24 hours atRT without further cooling. Subsequently, the batch is washed with 50 ml10% sodium hydroxide solution and 30 ml water. The organic phase isdried over sodium sulfate and the solvent is removed under vacuum. Thered brown residue is chromatographically purified three times oversilica gel with CHCl₃/CH₃OH (100/0, 97/3 and 96/4 to 94/6).Subsequently, a further purification occurs by means of MPLC withCHCl₃/CH₃OH (98/2). Yield: 0.5 g (5%) of a brittle, vitreous solid witha MP of 89-91° C. C₃₁H₃₅N₃OS (497.7) IR-spectrum (KBr): ν(NH) 3280cm⁻¹ν(C═O) 1660, 1550cm⁻¹ ν(C═C) 1620cm⁻¹ ¹H-NMR-spectrum (CDCl₃):0.90-2.00(13H, m, piperidine, piperidine-(CH₂)₃) 2.55-2.95(2H, m,piperidine) 3.20-3.60(3H, m, CONHCH ₂. SCH₂) 4.03(1H, Ar₂CH)6.10-6.35(1H, m, NH) 5.95-6.30(1H, m, SCH₂) 6.44(1H, d, CH═CHCO,J=15.7Hz) 6.85-7.40(9H, m, ar, py) 7.61(1H, d, CH═CHCO, J=15.7Hz)7.65-7.85(1H, m, py) 8.50-8.65(1H, m, py) 8.65-8.80(1H, m, py)

Example 6N-[4-(1-diphenylmethyl-piperidin-4-yl)-butyl]-5-(pyridin-3-yl)-2,4-pentadienoicacid amide (substance 70)

3.85 g (22.0 mmol) 5-(3-pyridyl)-2,4-pentadienoic acid are suspended in90 ml abs. dichlormethane and after addition of three drops of pyridine,cooled to ca. OC in an ice bath under moisture exclusion. 3.8 g (30.0mmol) oxalyl chloride are added dropwise and the mixture is stirred atRT overnight. Subsequently, the solvent and excess oxalyl chloride isdistilled off on a rotary evaporator. In order to completely remove theoxalyl chloride, the residue is dried for two hours under high-vacuum.The acid chloride obtained in this manner is suspended in 50 ml abs.dichloromethane and cooled to ca. 0° C. in an ice bath under moistureexclusion. 6.44 g (20.0 mmol)4-(1-diphenylmethyl-piperidin-4-yl)-butylamine are dissolved in 40 mlabs. dichlormethane and added dropwise to this suspension. Aftercomplete addition, the ice bath is removed and the reaction is stirredfor an additional two hours at RT. The mixture is subsequently washedwith 10% sodium hydroxide solution. The organic phase is washed twice,each with 40 ml water, dried over sodium sulfate and the solvent isremoved under vacuum. The residue is chromatographically purified oversilica gel with CHCl₃/CH₃OH (98/2 to 95/5) and crystallized twice from250 ml and 200 ml acetonitrile after drawing off the solvent. Beigecolored crystals with a MP of 164-166*C; yield: 4.7 g (49%). C₃₂H₃₇N₃O(479.6) IR-spectrum (KBr): ν(NH) 3280cm⁻¹ ν(C═O) 1650, 1550cm⁻¹ ν(C═C)1600cm⁻¹ ¹H-NMR-spectrum (CDCl₃): 1.00-2.00(13H, m, piperidine,piperidine-(CH₂)₃) 2.70-3.00(2H, m, piperidine) 3.34(2H, dt, CONHCH ₂.J=6.6Hz. J=12.8Hz) 4.21(1H, s, Ar₂CH) 5.50-5.75(1H, m, NH) 6.44(1H, d,CH═CH, J=14.7Hz) 6.75-6.95(2H, m, CH═CH) 7.05-7.50(12H, m, ar, py.CH═CH) 7.65-7.85(1H, m, py) 8.45-8.55(1H, m, py) 8.60-8.75(1H, m, py)

Example 7N-[4-(1-benzoylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide(substance 159)

5.1 g (36.2 mMol) benzoyl chloride are dissolved in 150 ml abs.dichlormethane and cooled to ca. 0° C. under moisture exclusion. 10.4 g(36.2 mmol) N-[4-(piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide(substance 14) are dissolved in 50 ml abs. dichlormethane and addeddropwise under ice cooling. The mixture is stirred overnight at RTwithout further cooling. Subsequently, the suspension is added to 60 ml2 M sodium hydroxide and extracted twice, each with 80 mldichlormethane. The combined organic phases are washed twice, each with60 ml water, dried over sodium sulfate and the solvent is removed undervacuum. The residue is chromatographically purified over silica gel withCHCl₃/CH₃OH (97/3 to 9515) and recrystalized from 75 ml acetonitrile.Colorless crystals with a MP of 100-102° C. are recovered; yield: 9.8 g(69%). C₂₄H₂₉N₃O₂ (391.5) IR-spectrum (KBr): ν(NH) 3280cm⁻¹ ν(C═O) 1670,1545cm⁻¹ ν(C═C) 1630cm⁻¹ ¹H-NMR-spectrum (CDCl₃): 0.80-2.00(11H, m,piperidine, piperidine-(CH₂)₃) 2.55-4.00(5H, m, piperidine, CONHCH ₂)4.40-4.90(1H, piperidine) 6.00-6.25(1H, m, NH) 6.48(1H, d, CH═CHCO,J=15.7Hz) 7.15-7.95(8H, m, ar, py. CH═CHCO) 8.50-8.65(1H, m, py)8.65-8.80(1H, m, py)

Example 8N-(1-diphenylmethyl-azetin-3-ylmethyl)-3-(pyridin-3-yl)acrylamide(substance 1)

Production occurs analogously to example 6.

Batch size: 4.3 g (28.7 mmol) 3-(3-pyridyl)-acrylic acid, 6.7 ml (78.4mmol) oxalyl chloride and 6.6 g (26.1 mmol)(1-diphenylmethyl-azetidin-3-ylmethyl)-amine.

In the work up, the reaction mixture is washed with 10% sodium hydroxidesolution. The aqueous phase is extracted twice, each with 50 nmldichlormethane. The combined organic phases are dried over sodiumsulfate and the solvent is removed under vacuum. The residue ischromatographically pre-purified over silica gel with CHCl₃/CH₃OH (98/2to 95/5) and subsequently purified by two-fold flash-chromatography withCHCl₃/CH₃OH (9911 to 95/5). After drawing off the solvent, an amorphoussolid remains with a MP of 72-74° C.; yield: 0,75-g (7%). C₂₅H₂₅N₃O(383.5) IR-spectrum (KBr): ν(NH) 3320cm⁻¹ ν(C═O) 1680, 1570cm⁻¹ ν(C═C)1640 cm⁻¹ ¹H-NMR-spectrum (CDCl₃): 2.40-2.80(1H, m, azetidine)2.80-3.10(2H, m, azetidine) 3.10-3.40(2H, m, azetidine) 3.60(2H, dd,CONHCH ₂. J=5.7Hz) 4.36(1H, Ar2CH) 6.45-6.75(1H, m, NH) 6.50(1H, d,CH═CHCO, J=15.7Hz) 7.00-7.50(11H, m, ar, py) 7.62(1H, d, CH═CHCO,J=15.7Hz) 7.65-7.90(1H, m, py) 8.50-8.70(1H, m, py) 8.70-8.85(1H, m, py)

Example 9N-(4-diphenylmethyl-morpholin-2-ylmethyl)-3-(pyridin-3-yl)-acrylamide(substance 250)

Production occurs analogously to example 6

Batch size: 2.3 g (15.6 mmol) 3-(3-pyridyl)-acrylic acid, 5.4 g (42.5mmol) oxalyl chloride and 3.6 g (14.7 mmol)2-aminomethyl-4-diphenylmethylmorpholine.

In the work up, 40 ml 10% sodium hydroxide solution are added to thereaction solution. The aqueous phase is extracted with 15 mldichlormethane. The combined organic phases are washed twice, each with15 ml water, dried over sodium sulfate and the solvent is removed undervacuum. The residue is chromatographically purified three times oversilica gel with CHCl₃/CH₃CH (95/5, 90/10 and 90/10). After drawing offthe solvent, an amorphous solid remains with a MP of 71-74° C.; yield:0.8 g (13%). C₂₆H₂₇N₃O₂ (413.5) IR-spectrum (KBr): ν(NH) 3270cm⁻¹ ν(C═O)1655, 1540cm⁻¹ ν(C═C) 1620cm⁻¹ ¹H-NMR-spectrum (CDCl₃): 1.70-2.30(2H, m,morpholine) 2.55-2.90(2H, m, morpholine) 3.00-3.35(1H, m, morpholine)3.50-4.00(4H, m, CONHCH ₂, morpholine) 4.20(1H, Ar₂CH) 6.00-6.25(1H, m,NH) 6.47(1H, d, CH═CHCO, J=15.7Hz) 7.00-7.55(11H, m, ar, py) 7.60(1H, d,CH═CHCO, J=15.7Hz) 7.65-7.90(1H, m, py) 8.50-8.70(1H, m, py)8.70-8.80(1H, m, py)

Example 10N-{4-[1-(9-oxo-9H-fluoren-4-yl-carbonyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide(substance 178)

5.0 g (20.0 mmol) 95% 9-fluorenon-4-carboxylic acid chloride aredissolved in 70 ml abs. dichlormethane and 6.5 g (18.2 mmol)N-[4-(piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide dihydrochloride(substance 14 as a dihydrochloride) are added. The mixture is cooled toca. 0° C. under moisture exclusion and 4.0 g (40.0 mmol) TEA dissolvedin 10 ml abs. dichlormethane are added dropwise. The batch is stirred atRT overnight without further cooling. In the work up, 150 ml 10% sodiumhydroxide solution are added to the reaction solution and this isextracted by shaking. The organic phase is washed with 100 ml water,dried over sodium sulfate and the solvent is removed under vacuum. Theresidue is pre-purified over silica gel with CHCl₃/CH₃OH (96/4 to 95/5)and subsequently purified by flash-Chromatography with CHCl₃/CH₃OH(95/5). After drawing off the solvent, the product remains as a yellowvitreous solid with a MP of 80-82° C.; yield: 2.3 g (25%). C₃₁H₃₁N₃O₃(493.6) IR-spectrum (KBr): ν(NH) 3320cm⁻¹ ν(C═O) 1730, 1640cm⁻¹ ν(C═C)1620cm⁻¹ ¹H-NMR-spectrum (CDCl₃): 0.70-2.05(11H, m, piperidine,piperidine-(CH₂)₃) 2.60-3.80(5H, m, piperidine, CONHCH ₂) 4.70-5.05(1H,piperidine) 5.85-6.20(1H, m, NH) 6.47(1H, d, CH═CHCO, J=15.7Hz)7.15-7.90(10H, m, ar, py. CH═CHCO) 8.50-8.65(1H, m, py) 8.65-8.85(1H, m,py)

Example 11N-[3-(1-benzyl-piperidin-4-yloxy)propyl]-3-(pyridin-3-yl)-acrylamide(substance 39)

2.4 g (16.2 mmol) 3-(3-pyridyl)-acrylic acid and 2.3 ml (16.2 mmol) TEAare suspended in 50 ml abs. toluene and a solution of 1.5 ml (15.5 mmol)chloroformic acid ethyl ester in 20 ml abs. toluene are added dropwiseunder moisture exclusion and light cooling. This yellow suspension isstirred at RT for two hours and then a solution of 3.5 g (14.1 mmol)3-(1-benzylpiperidin-4-yloxy)-propylamine in 20 ml abs. toluene is addeddropwise. The mixture is stirred for two hours at RT and extracted byshaking three times in the heat, each with 10 ml water, 2 M sodiumhydroxide and water again. The organic phase is concentrated undervacuum and the orange colored oily residue is chromatographicallypurified twice over silica gel with CHCl₃/CH₃OH/NH₄OH (90/9/1 and 95/5/0to 90/10/0) and crystallized from 10 ml acetic acid ethyl ester.Colorless crystals remain with a MP of 100-102° C.; yield: 1.9 g (35%).C₂₃H₂₉N₃O₂ (379.5) IR-spectrum (KBr): ν (NH) 3290 cm⁻¹ ν (C═O) 1650,1530 cm⁻¹ ν (C═C) 1610 cm⁻¹ ¹H-NMR-spectrum (CDCl₃): 1.50-2.45(8H, m,piperidine, C—CH₂—C) 2.70-3.00(2H, m, piperidine) 3.25-3.80(7H, m,piperidine, CONHCH ₂. Ar—CH₂. O—CH₂) 6.54(1H, d, CH═CHCO, J=15.7Hz)6.70-6.95(1H, m, NH) 7.25-7.50(6H, m, ar, py) 7.69(1H, d, CH═CHCO,J=15.7Hz) 7.80-8.00(1H, m, py) 8.60-8.75(1H, m, py) 8.75-8.90(1H, m, py)

Example 12N-[6-(1-diphenylmethyl-piperidin-3-yl-carbonyl-amineo)-hexyl]-3-(pyridin-3-yl)-acriyamide(substance 103)

1.79 g (12.0 mmol) 3-(3-pyridyl)-acrylic acid and 4,0 g (39.5 mmol) TEAare suspended in 80 ml abs. dichloromethane and cooled to ca. 0° C.under moisture exclusion. 2.2 g (14.3 mmol) 88% HOBT and 2.76 g (14.4mmol) EDC are added and the mixture is stirred 30 min under ice cooling.5.6 g (12.0 mmol) 1-diphenylmethyl-piperidin-3-carboxylicacid-(6-amino-hexyl)-amide dihydrochloride are added and the mixture isstirred overnight at RT without cooling. Subsequently, the batch iswashed twice with sodium hydroxide with 50 ml 2M sodium hydroxidesolution and 70 ml water. The organic phase is dried over sodium sulfateand the solvent is removed under vacuum. The residue ischromatographically purified over silica gel with CHCl₃/CH₃OH (96/4 to95/5) and crystallized from 70 ml acetonitrile. Colorless crystalsremain with aMP of 129-131° C.; yield: 3.9 g (62%). C₃₃H₄₀N₄O₂ (524.7)IR-spectrum (KBr): ν (NH) 3300 cm⁻¹ ν (C═O) 1640, 1540 cm⁻¹ ν (C═C) 1620cm⁻¹ ¹H-NMR-spectrum (CDCl₃): 1.20-2.95(17H, m, piperidine, C—(CH₂)₄—C)3.15-3.55(4H, m, CONHCH ₂) 4.24(1H, Ar₂CH) 6.30-6.55(1H, m, NH) 6.57(1H,d, CH═CHCO, J=15.7Hz) 7.05-7.45(11H, m, ar, py) 7.62(1H, d, CH═CHCO,J=15.7Hz) 7.65-8.00(2H, m, py. NH) 8.50-8.60(1H, m, py) 8.65-8.80(1H, m,py)

Example 13N-[4-(1-diphenylphosphiny-piperidin-yl)-butyl]-3-(pyridin-3-yl)-acrylamide(substance 232)

1.06 ml (5.55 mmol) diphenylphosphinic acid chloride are dissolved in 20ml abs. THF and cooled to ca. 0° C. under moisture exclusion. 2.0 g(5.55 mmol) N-[4-(piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamidedihydrochloride (substance 14 as a dihydrochloride) and 2.3 ml (16.6mmol) TEA are suspended in 90 ml abs. THF and added dropwise under icecooling. The mixture is stirred for four days at RT without furthercooling. Subsequently the solvent is removed under vacuum and theresidue is taken up in 70 ml 10% sodium hydroxide solution and extractedtwice, each with 100 ml CHCl₃. The combined organic phases are washedwith saturated NaCl solution, dried over sodium sulfate and the solventis removed under vacuum. The residue is pre-purifeid over silica gelwith CHCl₃/CH₃OH (90/10), subsequently further purified byflash-chromatography with CHCl₃/CH₃OH (90/10) and crystallized from 30ml acetic acid ethyl ester. Colorless crystals remain with a MP of154-155° C.; yield: 1.04 g (30%). C₂₉H₃₄N₃O₂P (487.6) IR-spectrum (KBr):ν (NH) 3260 cm⁻¹ ν (C═O) 1650, 1550 cm⁻¹ ν (C═C) 1610 cm⁻¹¹H-NMR-spectrum (CDCl₃): 0.90-1.80(11H, m, piperidine,piperidine-(CH₂)₃) 2.55-2.95(2H, m, piperidine) 3.10-3.55(4H, m,piperidine, CONHCH ₂) 6.59(1H, d, CH═CHCO, J=15.7Hz) 6.55-6.80(1H, m,NH) 7.15-8.00(13H, m, ar, py. CH═CHCO) 8.50-8.60(1H, m, py)8.60-8.80(1H, m, py)

Example 14N-[4-(1-benzyl-piperidin-3-yl)-butyl]-3-(pyridin-3-yl)-acrylamide(substance 40)

Production occurs analogously to example 6

Batch size: 2.6 g (17.4 mmol) 3-(3-pyridyl)-acrylic acid, 1.6 ml (19.0mmol) oxalyl chloride and 3.9 g (15.8 mmol)4-(1-benzyl-piperidin-3-yl)-butylamine in 100 ml abs. dichlormethane.

The reaction time is prolonged to 6 hours at RT. In the work up, thebatch is washed with 50 ml 1 M sodium hydroxide solution and the aqueousphase is extracted with 50 ml dichlormethane. The combined organicphases are concentrated under vacuum and the residue ischromatographically pre-purified twice over silica gel with CHCl₃/CH₃OH(93n and 9515), subsequently purified further by flash-chromatographywith CHCl₃/CH₃OH (9515 and 97/3) and crystallized from 5 ml acetic acidethyl ester. Colorless crystals remain with a MP of 80-82° C., yield:0.9 g (15%). C₂₄H₃₁N₃O (377.5) IR-spectrum (KBr): ν (NH) 3300 cm⁻¹ ν(C═O) 1650, 1530 cm⁻¹ ν (C═C) 1610 cm⁻¹ ¹H-NMR-spectrum (CDCl₃):1.00-2.10(13H, m, piperidine, piperidine-(CH₂)₃) 2.65-2.95(2H, m,piperidine) 3.37(2H, dt, CONHCH ₂. J=6.5Hz. J=12.7Hz) 3.50(2H, s,Ar—CH₂) 5.65-5.95(1H, m, NH) 6.46(1H, d, CH═CHCO, J=15.6Hz)7.10-7.40(6H, m, ar, py) 7.62(1H, d, CH═CHCO, J=15.6Hz) 7.65-7.90(1H, m,py) 8.50-8.65(1H, m, py) 8.70-8.80(1H, m, py)

Example 15N-[4(1-tert-Butoxycarbonylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide(substance 242)

Production occurs analogously to example 6. TEA is also added dropwisewith the addition of the amine.

Batch size: 16.4 g (110 mmol) 3-(3-pyridyl)-acrylic acid, 18.9 g (150mmol) oxalyl chloride, 25.6 g (100 mmol)4-(1-tert-butoxycarbonyl-piperidin-4-yl)-butylamine and 10.1 g (100mmol) TEA in 300 ml abs. dichlormethane.

In the work up, 100 ml 10% sodium hydroxide solution are added to thereaction solution. The aqueous phase is extracted with 30 mldichlormethane. The combined organic phases are washed twice, each with25 ml water, and the solvent is removed under vacuum. The residue sdissolved in CHCl₃/CH₃OH (90/10) and filtered through a thin silica gellayer. After drawing off the solvent, the crude product remains as a redoil (44.0 g). For purification, this is chromatographed with CHCJ₃/CH₃OH(95/5) on silica gel. Yield: 26.5 g (68%) as a yellow viscous oil.C₂₂H₃₃N₃O₃ (387.50) IR-spectrum (KBr): ν (NH) 3250 cm⁻¹ ν (C═O) 1670,1540 cm⁻¹ ν (C═C) 1600 cm⁻¹ ¹H-NMR-spectrum (CDCl₃): 0.80-1.90 (20H, m,piperidine, piperidine-(CH₂)₃, tert, butyl) 2.30-2.90 (2H, m,piperidine) 3.10-3.60 (2H, m, piperidine) 3.80-4.30 (2H, m, CONHCH ₂)6.15-6.55 (1H, m, NH) 6.43 (1H, d, CH═CHCO, J=15.6Hz) 7.0514 7.85 (2H,m, py) 7.51 (1H, d, CH═CHCO, J=15.6Hz) 8.35-8.55 (1H, m, py) 8.55-8.70(1H, m, py)

Example 16

N-[4-(piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide dihydrochloride(substrate 14 as a dihydrochloride)

44.0 g (<113.5 mmol) crudeN-{4-[N-(tert-butoxycarbonyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide(substance 242) are dissolved in 400 ml ethanol and added to 26.0 mlcone, hydrochloric acid. The mixture is heated to boiling for threehours and, after cooling, the solvent is removed under vacuum. Theyellow residue is crystallized from 500 ml isopropanol. Beige coloredcrystals remain with a MP of 178-188° C.; yield: 32.6 g (90%).C₁₇H₂₅N₃O•2 HCl (360.3) IR-spectrum (KBr): ν (NH) 3260 cm⁻¹ ν (C═O)1670, 1545 cm⁻¹ ν (C═C) 1630 cm⁻¹ ¹H-NMR-spectrum (D₂O): 0.95-1.95(11H,m, piperidine, piperidine-(CH₂)₃) 2.60-3.00(2H, m, piperidine)3.00-3.40(4H, m, piperidine, CONHCH ₂) 6.73(1H, d, CH═CHCO, J=15.9Hz)7.41(1H, d, CH═CHCO, J=15.9Hz) 7.80-8.00(1H, m, py) 8.50-8.65(2H, m, py)8.65-8.90(1H, m, py)

The invention is more closely illustrated by means of the furthersynethesis examples listed in the following Table 2, without restrictingthe invention. TABLE 2

Prepared compounds of formula (I) MP [° C.] Nr R¹ A D-E-G (solvent)¹ 1 HCH═CH

72-74 (amorph; CHCl₃/MeOH) 4 H CH═CH

164-165 (EE) 14 H CH═CH

140-142 (amorph; CH₂Cl₂) 14 H CH═CH

 178-188²(iPrOH) 15 H CH═CH—CH═CH

 197-202²(iPrOH) 39 H CH═CH

100-102 (EE) 40 H CH═CH

80-82 (EE) 54 H CH═CH

135-136 (EE) 59 H CH═CH

221-223 (MeOH) 62 H CH═CH

139-140 (EE) 63

ca. 205 (Zers.) (CHCl₃) 65 H

142-144 (MeCN) 70 H CH═CH—CH═CH

164-166 (MeCN) 97 H CH═CH

178-180 (EE) 103 H CH═CH

129-131 (MeCN) 107 H CH═CH

190-192 (MeCN) 134 H CH═CH

139-141 (EE) 136 H CH═CH

89-91 (amorph; CHCl₃/MeOH) 140 H CH═CH

Harz³ 150 H CH═CH

161 (EtOH/Et₂O) 151 H CH═CH—CH═CH

77-79 (EE/BuCl) 153 H CH═CH

105-106 (MeCN/MTBE) 159 H CH═CH

100-102 (MeCN) 162 H CH═CH—CH═CH

133-135 (EE/BuCl) 178 H CH═CH

80-82 (amorph; CHCl₃/MeOH) 195 H CH═CH

198-200 (iPrOH) 199 H CH═CH

132-134 (EE) 200 H CH═CH—CH═CH

146-148 (iPrOH) 219 H CH═CH

85-87 (amorph; CHCl₃/MeOH) 232 H CH═CH

154-155 (EE) 242 H CH═CH

Ol³ 243 H CH═CH—CH═CH

135-136 (EE) 250 H CH═CH

71-74 (amorph; CHCl₃/MeOH)Table annotation¹MeOH = methanolEE = ethyl acetateiPrOH = isopropanolMeCN = acetonitrileEtOH = ethanolEt₂O = diethyl etherBuCl = 1-chlorobutaneMTBE = methyl tert-butyl ether²as a dihydrochloride³purified by column chromatography

Several examples for the production of the starting compounds aredescribed in the following for the better illustration of the productionof the end products.

Synthesis of the Starting Compounds Example 1A4(1-tert-butoxycarbonyl-piperidin-4-yl)-butan-1-ol

100 g (458 mmol) 4-piperidin-4-yl-butan-1-ol hydrochloride are dissolvedin 120 ml water, added to 216 ml (1550 mmol) TEA and cooled to ca. 5-10°C. 122 g (559 mmol) di-tert-butyl dicarbonate are dissolved in 400 mlTHF and added dropwise within four hours under further cooling. Themixture is left to stand without further cooling at RT overnight.Subsequently, the THF is removed under vacuum to a large extent and theresidue is extracted twice, each with 300 ml and 200 ml CHCl₃respectively, and the combined organic phases are washed twice, eachwith 20 ml water. The solvent is removed under vacuum. The residue isdried under high-vacuum and processed further without additionalpurification. Yield: 136 g (102%).

Example 2A2-[4-(1-tert-butoxycarbonylpipendin-4-yl)-butyl]-isoindol-1,3-dione

136 g (<528 mmol) 4-[1-tert-butoxycarbonylpiperidin-4-yl)-butan-1-ol(crude product), 135.3 g (516 mmol) Triphenylphosphine and 75.9 g (516mmol) phthalimide are suspended in 1800 ml THF and 89.9 g (516 mmol)azodicarboxylic acid diethyl ester are added dropwise within three hoursunder protective atmosphere and light cooling (to ca. 15° C.). Themixture is left to stand at RT overnight without further cooling.

Subsequently, the solvent is removed under vacuum and the oily residueis dissolved in 500 ml acetic acid ethyl ester and held at 0° C.overnight. The sedimented precipitate is filtered and discarded. Thesolution is concentrated under vacuum and the oily residue is,chromatographically purified over silica gel with CHCl₃ and crystallizedfrom 200 ml isopropanol after drawing off the solvent. Colorlesscrystals remain with a MP of 100-102° C.; yield: 108.5 g (57%).

Example 3A 4-(1-tert-butoxycarbonylpiperidin-4-yl)-butylamine

113.0 g (292 mmol)2-[4-(1-tert-butoxycarbonylpiperidin-4-yl)-butyl]-isoindol-1,3-dione aredissolved in 600 ml ethanol, added to 29.3 g (585 mmol) hydrazinehydrate and heated to boiling for three hours. After cooling thesolution, the mixture is filtered and the filtrate is concentrated undervacuum. The residue is dispersed in the heat (ca. 50° C.) between 500 mltoluene and 500 ml 10% sodium hydroxide solution. The organic phase iswashed once with 50 ml 10% sodium hydroxide solution and twice, eachwith 50 ml water. The solvent is removed under vacuum and the residue isdried at 70° C. under high-vacuum and processed further withoutadditional purification.

Yield of colorless oil: 64.0 g (85%).

Example 4A (1-diphenylmethyl-azetidin-3-ylmethyl)-amine

A solution of 10.0 g (40 mmol) 1-diphenylmethyl-azetidin-3-carbonitrilein 20 ml abs. THF is added dropwise to a suspension of 3.1 g (80 mmol)lithium aluminium hydride in 80 ml abs. THF at RT and and stirredovernight. The batch is carefully added to 2 ml ethanol and filtered.The filtrate is concentrated under vacuum and dispersed between CHCl₃and water. The aqueous phase is extracted twice, each with 50 ml CHCl₃,and the combined organic phases are dried over sodium sulfate and thesolvent is removed under vacuum. The residue is chromatographicallypurified over silica gel with CHCl₃/CH₃OH/NH₄OH (90/10/0 to 90/10/1).Yield: 5.6 g (55%) of slowly hardening resin.

Example 5A 3-(1-benzylpiperidin-4-yloxy)-propylamine

0.0 g (40.9 mmol) 3-(1-benzylpiperidin-4-yloxy)-propionitrile aredissolved in 100 ml ethanol and added to a spatula tip of Raney-Nickel.The mixture is stirred at RT under hydrogen atmosphere until the uptakeof the theoritical amount of hydrogen (ca. two days). The mixture isfiltered from the catalyst and the solvent is removed under vacuum. Theresidue is distilled in a bulb tube apparatus. Yield of colorless oil:7.5 g (73%).

Example 6A 1-diphenylmethyl-piperidin-3-carboxylic acid hydrochloride

15.7 g (100 mmol) piperidin-3-carboxylic acid ethyl ester and 30.4 g(220 mmol) potassium carbonate are placed in 100 ml DMF and 24.1 gdiphenyl methyl bromide are added dropwise. The mixture is stirredovernight at RT and subsequently filtered. The filtrate is concentratedunder vacuum and the residue is taken up with 150 ml acetic acid ethylester and extracted twice, each with 50 ml 10% hydrochloric acid. Theorganic phase is discarded and the combined aqueous phases are madebasic with 10% sodium hydroxide solution and extracted twice, each with50 ml acetic acid ethyl ester. The combined organic phases are cooled toca. 0° C. and the precipitated solid is drawn off and dried. Yield: 20.5g (63%) of the compound 1-diphenylmethyl-piperidin-3-carboxylic acidethyl ester with a MP of 166-168° C. This compound is heated to boilingfor 8 hours together with 24 ml 20% hydrochloric acid in 100 ml water.After cooling, the precipitate is filtered and crystallized from 70 mlmethanol. Yield: 15.6 g (74%).

Example 7A 1-diphenylmethylpiperidin-3-carboxylicacid-(6-amineohexyl)-amide

10.0 g (33.8 mmol) 1-diphenylmethylpiperidin-3-carboxylic acidhydrochloride are reacted analogously to example 6 with 8.6 g (68 mmol)oxalyl chloride to the acid chloride. This is suspended in abs.dichlormethane and added to 6.64 g (30.7 mmol)N-(tert-butoxycarbonyl)-hexanediamine and 3.1 g (30.7 mmol) TEA andstirred at RT overnight. The mixture is subsequently concentrated, takenup in CHCl₃ and washed once with 50 ml 10% sodium hydroxide solution andtwice with 30 ml water each. The organic phase is dried over sodiumsulfate and the solvent is removed under vacuum. The residue ischromatographically purified over silica gel with CHCl₃/CH₃OH (100/0 to98/2) and dissolved in 80 ml ethanol. After addition of 6 ml conc.hydrochloric acid, the mixture is heated to boiling for 5 hours. Aftercooling, the solvent is removed under vacuum and the residue isazeotropically dehydrated twice, each with 30 ml toluene, andsubsequently dried under high-vacuum. The resin is further processedwithout additional purification Yield: 6.8 g (71%).

Example 8A 4-(1-benzylpiperidin-3-yliden)-butyronitrile

77.3 g (188.3 mmol) 3-cyanopropyl-triphenylphosphonium bromide aresuspended in 300 ml toluene and added to 22.0 g (191.9 mmol) potassiumtert-butylate. The mixture is cooled to ca 0° C. under moistureexclusion and a solution of 34.6 g (182.8 mmol) 1-benzyl-3-piperidone in50 ml toluene is added dropwise under cooling. The batch is left tostand overnight at ca. 0° C. and subsequently diluted with 200 mltoluene and washed twice, each with 100 ml water. The organic phase isextracted with 150 ml half concentrated hydrochloric acid. Subsequently,the aqueous phase is made basic with 200 ml 10% sodium hydroxidesolution and extracted twice, each with 250 ml toluene. The solvent isremoved under vacuum and the residue is chromatographically purifiedover silica gel with CHCl₃/CH₃OH (97/3). After drawing off the solvent,a light brown oil remains which is processed further without additionalpurification. Yield: 47.4 g (90%).

Example 9A 4-(1-benzylpiperidin-3-yl)-butylamine

8.0 g (33.3 mmol) 4-(1-benzypiperidin-3-yliden)-butyronitrile aredissolved in 80 ml ethanol and added to a spatula tip of Raney-Nickel.The mixture is stirred at ca. 50° C. under hydrogen atmosphere untilconsumption of the theoretischen amount of hydrogen to be taken up (ca.5 days). The mixture is filtrated from the catalyst and the solvent isremoved under vacuum. The residue is chromatographically purified twiceover silica gel with CHCl₃/CH₃OH/NH₄OH (90/10/1). After drawing off thesolvent, a colorlesss oil remains which is further processed withoutadditional purification. Yield: 3.9 g (47%).

The active ingredients according to the invention can be processed tothe desired medicaments in the form of their acid addition salts,hydrates or solvates individually or in combination with each other,optionally under addition of other active ingredients, for theindications tumor treatment or immunosuppression. In the case of thecombination of active ingredients according to the invention with othermedicinal forms, these can also optionally be separately present next toeach other in the medicine packaging, for example as tablets next toviles, depending on the requirements.

Therefore, further subject-matter of the invention is a method for thetreatment of the human or animal body in which a compound or compoundmixture according to formula (I), wherein the substituents have theabove described meaning, is administered for treatment of tumors and/oras a cytostatic agent, cancerostatic agent, immunosuppressing agent,optionally in combination with further cytostatic or immunosuppressiveactive ingredients or other active ingredients suitable in the namedindications.

Furthermore, the invention relates to a compound or compound mixtureaccording to formula (I) for use in a therapeutic method in which thetherapeutic use is carried out in connection with one or more medicalindications with tumors or for immunosuppression, optimally incombination with further pharmaceuticals suitable in the namedindications.

The use of one or more compounds according to formula (I), including(E)-3-(3-pyridyl)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-propenamidehydrochloride, for the production of medicaments for the treatment ofthe human or animal body, especially in connection with one or moremedical indications in the treatment of tumors or for immunosuppression,optimally in combination with further pharmaceuticals suitable in theseindications or the use of compounds according to formula (I) in acorresponding diagnosis method represent an embodiment according to theinvention.

The respective suitable tumor indications are illustrated in the lastsection of the description in the discussion of the pharmacological testresults.

A method for the production of medicaments with an amount of one or morecompounds according to formula (I) which are suitable for the processingof these active ingredients together with respective suitablepharmaceutically acceptable carriers and adjuvants for finishedmedicinal forms equally belongs to the scope of protection according tothe invention.

Depending on the medical indication being considered, the respectivesuitable medical form is selected for the suitable therapeuticapplication.

The invention also relates to the use of the compounds according toformula (I), including(E)-3-(3-pyridyl)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-propenamidehydrochloride, for treatment in the above indications.

The production of the respective suitable medicaments as well as aseries of examples of medicinal forms are described in the following forbetter understanding of the invention.

Therapeutic Administration Forms

The production of medicaments with an amount of one or more compoundsaccording to the invention and/or their use in the application accordingto the invention occurs in the customary manner by means of commonpharmaceutical technology methods. For this, the active ingredients assuch or in the form of their salts are processed together with suitable,pharmaceutically acceptable adjuvents and carriers to medicinal formssuitable for the various indications and types of application. Thereby,the medicaments can be produced in such a manner that the respectivedesired release rate is obtained, for example a quick flooding and/or asustained or depot effect.

Preparations for parenteral use, to which injections and infusionsbelong, are among the most important systemically employed medicamentsfor tumor treatment as well as for other indications.

Preferably, injections are administered for the treatment of tumors.These are prepared either in the form of vials or also as so-calledready-to-use injection preparations, for example as ready-to-usesyringes or single use syringes in addition to perforation bottles formultiple withdrawals. Administration of the injection preparations canoccur in the form of subcutaneous (s.c.), intramuscular (i.m.),intravenous (i.v.) or intracutaneous (i.c.) application. The respectivesuitable injection forms can especially be produced as solutions,crystal suspensions, nanoparticular or colloid-disperse systems, such asfor example, hydrosols.

The injectable formulations can also be produced as concentrates whichcan be adjusted with aqueous isotonic dilution agents to the desiredactive ingredient dosage. Furthermore, they can also be produced aspowders, such as for example lyophilisates, which are then preferablydissolved or dispersed immediately before application with suitablediluents. The infusions can also be formulated in the form of isotonicsolutions, fat emulsions, liposome formulations, microemuls ons andliquids based on mixed micells, for example, based on phospholipids. Aswith injection preparations, infusion formulations can also be preparedin the form of concentrates to dilute. The injectable formulations canalso be applied in the form of continuous infusions as in stationary aswell as in out-patient therapy, for example in the form of mini-pumps.

Albumin, plasma expanders, surface active compounds, organic solvents,pH influencing compounds, complex forming compounds or polymericcompounds can be added to the parenteral medicinal forms, especially assubstances for influencing the adsorption of the active ingredients toprotein or polymers or also with the aim of decreasing the adsorption ofthe active ingredient to materials such as injection instruments orpackaging materials, for example plastic or glass.

The active ingredients can be bound to nanoparticles in the preparationsfor parenteral use, for example on finely dispersed particles based onpoly(meth)acrylates, polyacetates, polyglycolates, polyamino acids orpolyether urethanes. The parenteral formulations can also beconstructively modified as depot preparations, for example on themultiple unit principle, where the active ingredients are incorporatedin a most finely distributed and/or dispersed, suspended form or ascrystal suspensions, or on the single unit principle, where the activeingredient is enclosed in a medicinal form, for example, a tablet or aseed which is subsequently implanted. Often, these implantations ordepot medicaments in single unit and multiple unit medicinal formsconsist of so-called biodegradable polymers, such as for example,polyether urethanes of lactic and glycolic acid, polyether urethanes,polyamino acids, poly(meth)acrylates or polysaccharides.

Sterilized water, pH value influencing substances, such as for exampleorganic and inorganic acids or bases as well as their salts, buffersubstances for setting the pH value, agents for isotonicity, such as forexample sodium chloride, monosodium carbonate, glucose and fructose,tensides and/or surface active substances and emulsifiers, such as forexample, partial fatty acid esters of polyoxyethylene sorbitan (Tween®)or for example fatty acid esters of polyoxethylene (Cremophor®), fattyoils such as for example peanut oil, soybean oil and castor oil,synthetic fatty acid esters, such as for example ethyl oleate, isopropylmyristate and neutral oil (Miglyol®) as well as polymer adjuvents suchas for example gelatin, dextran, polyvinylpyrrolidone, organic solventadditives which increase solubility, such as for example propyleneglycol, ethanol, N,N-dimethylacetamide, propylene glycol or complexforming compounds such as for example citrates and urea, preservatives,such as for example hydroxypropyl benzoate and hydroxymethyl benzoate,benzyl alcohol, anti-oxidants, such as for example sodium sulfite andstabilizers, such as for example EDTA, are suitable as adjuvents andcarriers in the production of preparations for parenteral use.

In suspensions, addition of thickening agents to prevent the settling ofthe active ingredients from tensides and peptizers, to secure theability of the sediment to be shaken, or complex formers, such as EDTA,ensues. This can also be achieved with the various polymeric agentcomplexes, for example with polyethylene glycols, polystyrol,carboxymethylcellulose, Pluronics® or polyethylene glycol sorbitan fattyacid esters. The active ingredient can also be incorporated in liquidformulations in the form of inclusion compounds, for example withcyclodextrins. As further adjuvents, dispersion agents are alsosuitable. For production of lyophilisates, builders are also used, suchas for example mannite, dextran, saccharose, human albumin, lactose, PVPor gelatin varieties.

As long as the active ingredients are not incorporated in the liquidmedicinal formulations in the form of a base, they are used in the formof their acid addition salts, hydrates or solvates in the preparationsfor parenteral use.

A further systemic application form of importance is peroraladministration as tablets, hard or soft gelatin capsules, coatedtablets, powders, pellets, microcapsules, oblong compressives, granules,chewable tablets, lozenges, gums or sachets. These solid peroraladministration forms can also be prepared as sustained action and/ordepot systems. Among these are medicaments with an amount of one or moremicronized active ingredients, diffisions and erosion forms based onmatrices, for example by using fats, wax-like and/or polymericcompounds, or so-called reservoir systems. As a retarding agent and/oragent for controlled release, film or matrix forming substances, such asfor example ethylcellulose, hydroxypropylmethylcellulose,poly(meth)acrylate derivatives (for example Eudragit®),hydroxypropylmethylcellulose phthalate are suitable in organic solutionsas well as in the form of aqueous dispersions. In this connection,so-called bio-adhesive preparations are also to be named in which theincreased retention time in the body is achieved by intensive contactwith the mucus membranes of the body. An example of a bio-adhesivepolymer is the group of Carbomers®.

For sublingual application, compressives, such as for examplenon-disintegrating tablets in oblong form of a suitable size with a slowrelease of active ingredient, are especially suitable. For purposes of atargeted release of active ingredients in the various sections of thegastrointestinal tract, mixtures of pellets which release at the variousplaces are employable, for example mixtures of gastric fluid soluble andsmall intestine soluble and/or gastric fluid resistant and largeintestine soluble pellets. The same goal of releasing at varioussections of the gastrointestinal tract can also be conceived by suitablyproduced laminated tablets with a core, whereby the coating of the agentis quickly released in gastric fluid and the core of the agent is slowlyreleased in the small intestine milieu. The goal of controlled releaseat various sections of the gastrointestinal tract can also be attainedby multilayer tablets. The pellet mixtures with differentially releasedagent can be filled into hard gelatin capsules.

Anti-stick and lubricant and separating agents, dispersion agents suchas flame dispersed silicone dioxide, disintegrants, such as variousstarch types, PVC, cellulose esters as granulating or retarding agents,such as for example wax-like and/or polymeric compounds on the basis ofEudragit®, cellulose or Cremophor® are used as a further adjuvents forthe production of compressives, such as for example tablets or hard andsoft gelatin capsules as well as coated tablets and granulates.

Anti-oxidants, sweetening agents, such as for example saccharose, xyliteor mannite, masking flavors, aromatics, preservatives, colorants, buffersubstances, direct tableting agents, such as for examplemicrocrystalline cellulose, starch and starch hydrolysates (for exampleCelutab®), lactose, polyethylene glycols, polyvinylpyrrolidone anddicalcium phosphate, lubricants, fillers, such as lactose or starch,binding agents in the form of lactose, starch varieties, such as forexample wheat or corn and/or rice starch, cellulose derivatives, forexample methylcellulose, hydroxypropylcellulose or silica, talcumpowder, stearates, such as for example magnesium stearate, aluminumstearate, calcium stearate, talc, siliconized talc, stearic acid, acetylalcohol and hydrated fats are used.

In this connection, oral therapeutic systems constructed especially onosmotic principles, such as for example GIT (gastrointestinaltherapeutic system) or OROS (oral osmotic system), are also to bementioned.

Effervescent tablets or tabs. both of which represent immediatelydrinkable instant medicinal forms which are quickly dissolved orsuspended in water are among the perorally administratable compressives.Among the perorally administratable forms are also solutions, forexample drops, juices and suspensions, which can be produced accordingto the above given method, and can still contain preservatives forincreasing stability and optionally aromatics for reasons of easierintake, and colorants for better differentiation as well as antioxidantsand/or vitamins and sweeteners such as sugar or artificial sweeteningagents. This is also true for inspisated juices which are formulatedwith water before ingestion. Ion exchange resins in combination with oneor more active ingredients are also to be mentioned for the productionof liquid ingestable forms.

A special release form consists in the preparation of so-called floatingmedicinal forms, for example based on tablets or pellets which developgas after contact with body fluids and therefore float on the surface ofthe gastric fluid. Furthermore, so-called electronically controlledrelease systems can also be formulated by which active ingredientrelease can be selectively adjusted to individual needs.

A further group of systemic administration and also optionally topicallyeffective medicinal forms are represented by rectally applicablemedicaments. Among these are suppositories and enema formulations. Theenema formulations can be prepared based on tablets with aqueoussolvents for producing this administration form. Rectal capsules canalso be made available based on gelatin or other carriers.

Hardened fat, such as for example Witepsol®, Massa Estarinum®D, Novata®,coconut fat, glycerol-gelatin masses, glycerol-soap-gels andpolyethylene glycols are suitable as suppository bases.

For long-term application with a systematic active ingredient release upto several weeks, pressed implants are suitable which are preferablyformulated on the basis of so-called biodegradable polymers.

As a further important group of systemically active medicaments,transdermal systems are also to be emphasized which distinguishthemselves, as with the above-mentioned rectal forms, by circumventingthe liver circulation system and/or liver metabolism. These plasters canbe especially prepared as transdermal systems which are capable ofreleasing the active ingredient in a controlled manner over longer orshorter time periods based on different layers and/or mixtures ofsuitable adjuvents and carriers. Aside from suitable adjuvents andcarriers such as solvents and polymeric components, for example based onEudragit®, membrane infiltration increasing substances and/or permeationpromoters, such as for example oleic acid, Azone®, adipinic acidderivatives, ethanol, urea, propylglycol are suitable in the productionof transdermal systems of this type for the purpose of improved and/oraccelerated penetration.

As topically, locally or regionally administration medicaments, thefollowing are suitable as special formulations: vaginally or genitallyapplicable emulsions, creams, foam tablets, depot implants, ovular ortransurethral adminstration installation solutions. For opthalmologicalapplication, highly sterile eye ointments, solutions and/or drops orcreams and emulsions are suitable.

In the same manner, corresponding otological drops, ointments or creamscan be designated for application to the ear. For both of theabove-mentioned applications, the adminstration of semi-solidformulations, such as for example gels based on Carbopols® or otherpolymer compounds such as for example polyvinylpyrolidone and cellulosederivatives is also possible.

For customary application to the skin or also to the mucus membrane,normal emulsions, gels, ointments, creams or mixed phase and/oramphiphilic emulsion systems (oil/water-water/oil mixed phase) as wellas liposomes and transfersomes can be named. Sodium algenate as a gelbuilder for production of a suitable foundation or celluolosederivatives, such as for example guar or xanthene gum, inorganic gelbuilders, such as for example aluminum hydroxides or bentonites(so-called thixotropic gel builder), polyacrylic acid derivatives, suchas for example Carbopol®, polyvinylpyrolidone, microcrystallinecellulose or carboxymethylcellulose are suitable as adjuvents and/orcarriers. Furthermore, amphiphilic low and high molecular weightcompounds as well as phospholipids are suitable. The gels can be presenteither as hydrogels based on water or as hydrophobic organogels, forexample based on mixtures of low and high molecular paraffinhydrocarbons and vaseline.

Anionic, cationic or neutral tensides can be employed as emulsifiers,for example alkalized soaps, methyl soaps, amine soaps, sulfanatedcompounds, cationic soaps, high fatty alcohols, partial fatty acidesters of sorbitan and polyoxyethylene sorbitan, for example lanettetypes, wool wax, lanolin, or other synthetic products for the productionof oil/water and/or water/oil emulsions.

Hydrophilic organogels can be formulated, for example, on the basis ofhigh molecular polyethylene glycols. These gel-like forms are washable.Vaseline, natural or synthetic waxes, fatty acids, fatty alcohols, fattyacid esters, for example as mono-, di-, or triglycerides, paraffin oilor vegetable oils, hardened castor oil or coconut oil, pig fat,synthetic fats, for example based on acrylic, caprinic, lauric andstearic acid, such as for example Softisan® or triglyceride mixturessuch as Miglyol®. are employed as lipids in the form of fat and/or oiland/or wax-like components for the production of ointments, creams oremulsions.

Osmotically effective acids and bases, such as for example hydrochloricacid, citric acid, sodium hydroxide solution, potassium hydroxidesolution, monosodium carbonate, further buffer systems, such as forexample citrate, phosphate, Tris-buffer or triethanolamine are used foradjusting the pH value.

Preservatives, for example such as methyl- or propyl benzoate(parabenes) or sorbic acid can be added for increasing stability.

Pastes, powders or solutions are to be mentioned as further topicallyapplicable forms. Pastes often contain lipophilic and hydrophilicauxiliary agents with very high amounts of fatty matter as aconsistency-giving base.

Powders or topically applicable powders can contain for example starchvarieties such as wheat or rice starch, flame dispersed silicon dioxideor silica, which also serve as diluents, for increasing flowability aswell as lubricity as well as for preventing agglomerates.

Nose drops or nose sprays serve as nasal application forms. In thisconnection, nebulizers or nose creams or ointments can come to use.

Furthermore, nose spray or dry powder formulations as well as controlleddosage aerosols are also suitable for systemic administration of theactive ingredients.

These pressure and/or controlled dosage aerosols and dry powderformulations can be inhaled and/or insufflated. Administration forms ofthis type also certainly have importance for direct, regionalapplication in the lung or bronchi and larynx. Thereby, the dry powdercompositions can be formulated for example as active ingredient-softpellets, as an active ingredient-pellet mixture with suitable carriers,such as for example lactose and/or glucose. For inhalation orinsufflation, common applicators are suitable which are suitable for thetreatment of the nose, mouth and/or pharynx. The active ingredients canalso be applied by means of an ultrasonic nebulizing device. As apropellant gas for aerosol spray formulations and/or controlled dosageaerosols, tetrafluoroethane or BFC 134a and/or heptafluoropropane or HFC227 are suitable, wherein non-fluorinated hydrocarbons or otherpropellants which are gaseous at normal pressure and room temperature,such as for example propene, butane or dimethyl ether can be preferred.Instead of controlled dosage aerosols, propellant-free, manual pumpsystems can also be used.

The propellant gas aerosols can also suitably contain surface activeadjuvents, such as for example isopropyl myristate, polyoxyethylenesorbitan fatty acid ester, sorbitan trioleate, lecithins or soyalecithin.

For regional application in situ, solutions for installation, forexample for transurethral administration in bladder tumors or genitaltumors, or for profusion in liver tumors or other organ carcinomas aresuitable.

The respective suitable medicinal forms can be produced in accordancewith the prescription and procedures based on pharmaceutical-physicalfundamentals as they are described for example in the followinghandbooks and are included in the present inventive subject-matter withrespect to the production of the respective suitable medicaments:

-   Physical Pharmacy (A. N. Martin, J. Swarbrick, A. Cammarata), 2nd    Ed., Philadelphia Pa., (1970), German version: Physikalische    Pharmazie, (1987), 3rd edition, Stuttgart;-   R. Voigt, M. Bornschein, Lehrbuch der pharmazeutischen Technologie,    Verlag Chemie, Weinbeim, (1984), 5th edition;-   P. H. List, Arzneimformenlehre, Wissenschaftliche    Verlagsgesellschaft mbH, Stuttgat, (1985), 4th edition;-   H. Sucker, P. Fuchs, P. Speiser, Pharmazeutische Technologie, Georg    Thieme Verlag, Stuttgart—New York, (1991), 2nd edition;-   A. T. Florence, D. Attwood, Physicochemical Principits of Pharmacy,    The Maximillan Press Ltd., Hong Kong, (1981);-   L. A. Trissel, Handbook on Injectable Drugs, American Society of    Hospital Pharmacists, (1994), 8th edition;-   Y. W. Chien, Transdermal Controlled Systemic Medications, Marcel    Dekker Inc., New York—Basel, (1987);-   K. E. Avis, L. Lachmann, H. A. Liebermann, Pharmaceutical Dosage    Forms: Parenteral Medications, volume 2, Marcel Dekker Inc., New    York—Basel, (1986);-   B. W. Müller, Controlled Drug Delivery, Paperback APV, volume 17,    Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, (1987);-   H. Asch, D. Essig, P. C. Schmidt, Technologie von Salben,    Suspensionen und Emulsionen, Wissenschaftliche Verlagsgesellschaft    mbH, Stuttgart, (1984);-   H. A. Liebermann, L. Lachman, J. B. Schwartz, Pharmaceutical Desage    forms: Tablets, Volume 1, Marcel Dekker Inc., New York, 2nd Edition    (1989);-   D. Chulin, M. Deleuil, Y. Pourcelot, Powder Technology and    Pharmaceutical Processes, in J. C. Williams, T. Allen, Handbook of    Powder Technology, Elsevier Amsterdam—London—New York—Tokyo, (1994);-   J. T. Carstensen, Pharmaceutical Principles of Solid Dosage Forms,    Technomic Publishing Co., Inc., Lancaster—Basel, (1993).

PRODUCTION EXAMPLES

1. Injection Therapeutics

a) Parenteral Solution active ingredient used according to the invention5.000 g acid sodium phosphate 5.000 g sodium tartrate 12.000 g benzylalcohol 7.500 g water for injection purposes to 1000.000 ml

The solution is produced according to the customary method, sterilizedand filled into 10 ml vials. One vial contains 50 mg of the compoundaccording to the invention.

b) Penteral Solution active ingredient used according to the invention1.000 g hydrochloric acid, dilute 5.000 g sodium chloride 6.000 g waterfor injection purposes to 1000.000 ml

The solution is produced according to a customary method by stirring;the medicinal form is adjusted to a suitable pH value by acid additionand subsequently filled into 100 ml vials and sterilized. A vialcontains 100 mg of the compound according to the invention.

c) Parenteral Dispersion active ingredient used according to theinvention 10.000 g soya lecithin 20.000 g saturated triglycerides100.000 g sodium hydroxide 7.650 g water for injection purposes to1000.000 ml

The active ingredient(s) used according to the invention is dispersed inthe saturated triglycerides. Then the soya lecithin is added understirring, and subsequent to this, the aqueous solution of sodiumhydroxide is added with subsequent liomogenization. The dispersion issterilized and filled into 10 ml vials. A vial contains 50 mg of thecompound according to the invention.

d) Biodegradable Parenteral Depot Medicinal Form active ingredient usedaccording to the invention 10.000 polylactic acid/polygylcolic acidpolymer 70.000 polyvinylpyrrolidone 0.200 gelatin 2.000 soya lecithin2.000 isotonic sodium chloride solution to 1000.000 ml

First, the active ingredient is incorporated into the biodegradablepolymer comprising polylactic acid and polyglycolic acid by a suitablemethod (spray drying, solvent-evaporation or phase separation) andsubsequently subjected to a sterilization process. The particles areintroduced into a 2-chamber ready-made syringe in which the adjuventsolution, which is also produced in a sterile manner, is filled. Thebiodegradable microparticles are mixed with the dispersion agent shortlybefore application and dispersed. A ready-made syringe contains 200 mgof the active compound according to the invention.

e) Parenteral Dispersion for Subcutaneous Installation active ingredientused according to the invention 25,000 g soya lecithin 25,000 g arachisoil 400,000 g benzyl alcohol 50,000 g Miglyole ® to 1000,000 g

The active ingredient is dispersed together with soya lecithin andarachis oil. The benzyl alcohol is dissolved in Miglyole® and added tothe dispersion. The entire dispersion is sterilized and subsequentlyfilled into vials with 2 ml content. A vial contains 50 mg activeingredient.

f) Parenteral Perfusions Solution

The solution named under example b) can also be used for perfusion ofliver for example.

According to need, instead of ampules with injection solution, so-calledperforation bottles (vials), which can also be optionally preserved, andinfusion solutions with an amount of one or more active ingredientsaccording to the invention can also be made available in the customarymanner under addition of buffer substances for adjustment ofphysiological pH value and/or the isotonicity and/or a best possiblesuitable pH value for the medicinal form (euhydria) and optional furtherrequired nutrients, vitamins, amino acids, stablizers and othernecessary adjuvents, possibly in combination with further medicinalagents suitable for the mentioned indications.

2. Solid, Peroral Administration Medicaments

a) Tablets active ingredient used according to the invention 10,000 glactose 5,200 g starch, soluble 1,800 g hydroxypropylmethylcellulose 900g magnesium stearate 100 g

The above components are mixed with each other and compacted in aconventional manner, wherein a tablet weight of 180 mg is set. Eachtablet contains 100 mg active ingredient. If desired, the tabletsobtained in this manner are coated, provided with a film coat and/orenterically coated.

b) Coated Tablet Core active ingredient used according to the invention10,000 g flame dispersed silicon dioxide 500 g corn starch 2,250 gstearic acid 350 g ethanol 3.0 l gelatin 900 g purified water 10.0 ltalcum 300 g magnesium stearate 180 g

From these components, a granulate is produced which is pressed to thedesired coated tablet cores. Each core contains 50 mg of activeingredient. The core can be further processed in a customary manner tocoated tablets. If desired, a gastric fluid resistant or retarding filmcoat can be applied in a known manner.

c) Drink Suspension in Vials active ingredient used according to theinvention 0.050 g glycerin 0.500 g sorbite, 70% solution 0.500 g sodiumsaccharinate 0.010 g methyl-p-hydroxybenzoate 0.040 g aromatic agentq.s. sterile wasser q.s. to 5 ml

The above-mentioned components are mixed in a customary manner to asuspension and filled in a suitable drink vial having 5 ml content.

d) Poorly Soluble Sublingual Tablets active ingredient used according tothe invention 0.030 g lactose 0.100 g stearic acid 0.004 g talcum purum0.015 g sweetener q.s. aromatic agent q.s. rice starch q.s. to 0.500 g

The active ingredient is compacted together with the adjuvents underhigh pressure to sublingual tablets, favorably in oblong form.

e) Soft Gel Capsule active ingredient used according to the invention0.050 g fatty acid glyceride mixture (Miglyole ®) q.s. to 0.500 g

The active ingredient is impasted together with the fluid carriermixture and mixed together with further adjuvents suitable for theincapsulation and filled into elastic soft gelatin capsules which aresealed.

i) Hard Gelatin Capsules active ingredient used according to theinvention 0.150 g microcrystalline cellulose 0.100 ghydroxypropylmethylcellulose 0.030 g mannite 0.100 g ethylcellulose0.050 g triethyl citrate 0.010 g

The active ingredient is mixed together with the adjuvents,microcrystalline cellulose, hydroxypropylmethylcellulose and mannite,wet with granulation liquid and formed into pellets. These aresubsequently coated with a solution of ethylcellulose and triethylcitrate in organic solvents in a fluidized-bed apparatus. A hard gelatincapsule contains 150 mg of active ingredient.

3. Topically Administratable Medicinal Forms

a) Hydrophilic Ointment active ingredient used according to theinvention 0.500 g Eucerinum ® anhydricum 60.000 g microcrystalline wax15.000 g vaseline oil q.s. to 100.000 g

The above-mentioned adjuvents are melted and further processed togetherwith the active ingredient to an ointment in a customary manner.

b) Lipophilic Ointment active ingredient used according to the invention10.000 g propylene glycol 50.000 g paraffin, liquid 100.000 g paraffinwax 100.000 g vaseline to 1000.000 ml

The active ingredient(s) used according to the invention is dissolved inpropylene glycol at ca. 60° C. At the same time, the lipophiliccomponents are melted at 60-70° C. and subsequently combined with theactive ingredient solution. The ointment is emulsified at first at60-70° C. and subsequently cooled to 35-40° C. under constantemulsification and then filled in 10 g tubes. A tube contains 100 mg ofthe compound according to the invention.

4. Inhalation Therapeutic

Further subject-matter is a pharmaceutical formulation which ischaracterized in that it contains an active ingredient(s) used accordingto the invention as a base or a physiologically acceptable salt thereoftogether with carriers and/or diluents customary for this and suitablefor administration by means of inhalation.

In connection with the production of the medicaments, particularlysuitable physiologically acceptable salts of the active ingredients are,as already illustrated in the synthesis section, acid addition saltsderived from inorganic or organic acids such as for example especiallyhydrochloride, hydrobromide, sulfate, phosphate, maleate, tartrate,citrate, benzoate, 4-methoxybenzoate, 2- or 4-hydroxybenzoate,4-chlorobenzoate, p-tosylate, methaneosulfonate, ascorbate, salicylate,acetate, formate, succinate, lactate, glutarate, gluconate ortricarballylate.

The administration of the active ingredient(s) used of the invention bymeans of inhalation occurs according to the invention in conventionalways customary for administrations of this form, for example in the formof a commercial controlled dosage aerosol or in combination with aspacer. In controlled dosage aerosols, a metering valve is deliveredwith whose help, a dosed amount of the composition is administered. Forspraying, the present compositions can be formulated for example asaqueous solutions or suspensions and be administered by means of anatomizer. Aerosol spray formulations in which the zctive ingredient iseither suspended with one or two stabilizers in a propellant as acarrier and/or diluent, for example tetrafluoroethane or HFC 134a and/orheptafluoropropane or HFC 227 can equally be used, whereby however,non-fluorinated hydrocarbons or other propellants which are gaseous atnormal pressure and room temperature, such as propane, butane ordimethyl ether, can be preferred. Thereby, propellant-free manual pumpsystems or dry powder systems as described below can also be used.

Suitably, the propellant aerosols can also contain surface activeadjuvents, such as for example isopropyl myristate, polyoxyethylenesorbitan fatty acid ester, sorbitan trioleate, lecithins, oleic acid.

For administration by means of inhalation and/or insufflation, themedicaments with an amount of compounds according to the invention canalso be formulated in the form of dry powder compositions, for exampleas active ingredient-soft pellets or as an active ingredient-powdermixture with a suitable carrier, such as for example lactose and/orglucose. The powder compositions can be formulated and administered assingle doses or as multiple doses.

The compounds according to the invention are preferably administered bymeans of a controlled dosage aerosol or in the form of a dry powderdosage formulation, wherein the latter preferably contains glucoseand/or lactose as a carrier substance.

As applicators for inhalation of the pharmaceutical formulationscontaining one or more of the active ingredient(s) used according to theinvention, all applicators are generally suitable which are suitable forcontrolled dosage aerosols and/or a dry powder dosage formulation, suchas for example usual applicators for the nose, mouth and or pharynx, oralso devices standing under propellant gas for the delivery of a spray(as controlled dosage aerosol or dry powder dosage formulation) as theyare also used for inhalations in the nose, mouth and/or pharynx.

A further embodiment can also consist of an aqueous solution of theactive ingredient(s) used according to the invention, which alsooptionally contains further active ingredients and/or additives, whichare applied by means of an ultrasound atomizer. Intended dose peraerosol per stroke % by weight a) Controlled Dosage Aerosol activeingredient used according 0.500 mg 0.66 to the invention stabilizer0.075 mg 0.10 HFC 134a 75.500 mg  99.24 b) Controlled Dosage Aerosolactive ingredient used according 0.250 mg 0.32 to the inventionStabilizer 0.038 mg 0.05 HFC 227 79.180 mg  99.63

In the examples a) and b) the micronized active ingredient is, afterprevious dispersion in a small amount of the stabilizer, placed in asuspension vessel in which the bulk amount of propellant gas solution isfound. The corresponding suspension is dispersed by means of a suitablestirring system (for example high performance mixer or ultrasound mixer)until an ultra-fine dispersion results. The suspension is thencontinuously held in flux in a filling apparatus suitable for coldpropellants or pressure fillings. Alternatively, the suspension can alsobe produced in a suitable cooled stabilizer solution in HFC 134a/227.

The examples c) to d) describe the composition and production of dosagedry powder formulations. mg/dose c) Dosage-Dry Powder Formulation activeingredient used according to the invention 0.500 mg d) Dosage-Dry PowderFormulation active ingredient used according to the invention 0.500 mglactose Ph.Eur. to 2.5 mg or to 5.0 mg e) Dosage-Dry Powder Formulationactive ingredient used according to the invention 0.250 mg lactosePh.Eur. to 2.5 mg or to 5.0 mg

In example c) the active ingredient is formulated after micronizationunder addition of steam as pellets with an MMAD between 0.1 and 0.3 mmdiameter and brought to use in a multi-dose powder applicator.

In the examples d) and e) the active ingredient is micronized,thereafter, bulk material is mixed with the lactose in the givenamounts, and subsequently, filled in a multi-dose powder inhilator.

In all of the examples set forth above, the active ingredient or themedicinal agent in the form of the respective suitable pharmaceuticalacceptable salt and/or acid addition salts can be present, insofar asthe base is not preferred in each case.

In the following, the pharmaceutical test results obtained in connectionwith the newly found indications based, in a representative manner, onthe specifically structured new compounds are described.

Pharmaceutical Experimental Section

1. Growth Inhibition of Human Tumor Cells

The tumor growth inhibiting activity of the substances was determined onhuman tumor cells in standardized in vitro test systems. In thescreening tests, the substances gave IC₅₀-values in a concentrationrange of 0.1 nM to 10 μM.

Example

HepG2 cells plated at a density of 20,000 cells/ml in 12-well plasticdishes. Cultivation occured in Richters IMEM-ZO nutrient medium with 5%fetal calf serum (FCS) in a tissue culture incubator with a gas mixtureof 5% CO₂ and 95% air at a temperature of 37° C. One day after plating,the culture medium was aspirated from the cells and replaced by freshmedium which contained the respective concentrations of the testsubstances. For the individual concentrations and the controls withouttest substances, three-fold batches were done for each. Three days afterthe beginning of treatment, the medium was again renewed with the testcompounds. After six days of substance incubation, the test was endedand the protein amount in the individual wells was determined with thesulforhodamin-B-method (according to P. Skehan et al.; New ColorimetricCytotoxicity Assay for Anticancer-Drug Screening. J. Natl, Cancer Inst82: 1107-1112, 1990). The IC₅₀-values (defined as that concentration inwhich the cell growth was inhibited by 50%) was taken from thedose-response curves and given as a comparative measurement for theactivity of the test compounds.

The following results were obtained: Test substance No. IC₅₀-value [μM]136 0.002 153 0.002 159 0.0005 178 0.0007 199 0.0012. Iodications

The compounds of formula (I) and their salts permit a therapeutic use inmalignant illness of humans and animals through their excellentinhibition of the growth of tumor cells. The anti-neoplastic activity ofthe described substances can be used for prophylactic, adjunct,palliative, and curative treatment of solid tumors, leukemic illnessesand lymphomas as well as for decreasing or preventing metastasisformation in humans and animals. The therapeutic use is possible in thefollowing illnesses for example: gynocological tumors, such as of theuterus or the vagina, ovarian carcinomas, testicle tumors, prostatecarcinomas, skin cancer, kidney cancer, bladder tumors, esophaguscarcinomas, stomach cancer, rectal carcinomas, pancreas carcinomas,thyroid cancer, adrenal tumors, leukemia and lymphomas, Hodgkin'sdisease, tumor illnesses of the CNS, soft-tissue sarcomas, bonesarcomas, benign and malignant mesotheliomas, but especially intestinecancer, liver cancer, breast cancer, bronchial and lung carcinomas,melanomas, acute and chronic leukemias. Benign papillomatosis tumors arealso considered for therapy with the named substances.

The novel structural class of compounds possesses an independentactivity profile in the effectiveness against the various tumor types.Thus, tumors which are resistant to customary cytostatic agents, forexample, can respond entirely to these substances. In addition, based onthe independent characteristics, combinations of the new compounds withknown chemo-therapeutically used pharmaceuticals or other methods oftreatment are considered as long as their properties are complimented ina suitable manner. The integration of the presently used compounds withtheir specific structures in a therapy scheme is successful with one ormore substances from the following classes for example: anti-metabolites(for example cytarabine, 5-fluorouracil, 6-mercaptopurine,methotrexate), alkylating agents (for example busulfan, carmustine,cisplatin, carboplatin, cyclophosphamide, dacarbazine, melphalane,thiotepa), DNA-intercalating substances and topoisomerase inhibitors(for example actinomycin D, daunorubicin, doxorubicin, mitomycin C,mitoxantrone, etoposide, teniposide, topotecan, irinotecan), spindlepoisons (for example vincristine, navelbin, taxol, taxoter), hormonallyactive agents (for example tamoxifen, flutamide, formestan, goserelin)or other cytostatic agents with complex modes of action (for exampleL-asparaginase, bleomycin, hydroxyurea). Resistant tumor cells can bemade sensitive again by interaction of the new compounds with amechanism of resistance for common cytostatic agents (for exampleP-glycoprotein, MRP, glutathione-S-transferase, metallothionein). Acombination is also applicable with radiation therapy, hyperthermia orimmunotherapy, for example.

J. Immuno Suppressing Activity

Many anti-tumor agents have not only a cytotoxic effect on tumor cells,but also on the blood cell system. This leads to a weakening of theimmune defence, which can, in turn, be specifically employed to suppressthe rejection reaction after an organ transplantation for example.Therefore, a use of the main compounds, optionally in combination withother compounds effective for these indications is suitable in diseasessuch as psoriasis or autoimmune diseases. In order to test thepossibility for a therapeutic use in illnesses of this type, thesubstance activity was tested on freshly isolated lymphocytes asfollows:

The spleen of a Swiss mouse served as a lymphocyte source. Thelymphocyte population was isolated from the spleen cell suspension overa ficoll gradient and taken up in IMEM-ZO culture medium with 0,1%dextran 70,000 and 2% fetal calf serum. The cells were plated at adensity of ca. 500,000 cells/well/ml in a 12-well plate, 1 ml doublyconcentrated test substance solution was pipetted per well and this wassubsequently incubated in a tissue culture incubator at 37° C. and 5%CO₂. After 2 days, a 1 ml-aliquot with 5 μl of the fluorescent dyesolutions propidium iodide (8 mg/ml) and 3,3′-dihexyloxacarbocyaniniodide (40 μg/ml) each was added per well, and incubated for 3 minutesat room temperature. Subsequently, 10,000 cells per each sample weremeasured on a flow-through cytometer and the percentage amount of vitalcells in the population was determined. By means of the dose-responsecurves, IC₅₀-values were calculated which were also employed in thefollowing Tables for the characterization of the individual substances:Test Substance No. IC₅₀ [μM] 150 0.0002 153 0.00008 159 0.003 195 0.002199 0.00004

The independent class of the compounds used according to the inventionalso permits an efficient combination with known immunosuppressiveagents such as for example cyclosporin A, tacrolimus, rapamycin,azathioprin and glucocorticoids.

The invention is in no way limited to the present respective concretelynamed active ingredient concentrations, dosages, combinations with oneor more other cytostatic agents, tumor inhibitors, cancerostatic agents,immunosuppressive agents or further medicinal agents suitable for therespective specific indications or the type of tumor to treated orimmunological illness, etc.

1. Compounds of formula (I)

wherein R¹ hydrogen, halogen, cyano, trifluoromethyl, hydroxy,benzyloxy, aminocarbonyl, carboxy, phenyl, phenoxy, phenylthio,pyridyloxy, pyridylthilo, alkyl, especially C₁-C₆-alkyl, alkenyl,especially C₃-C₆-alkenyl, alkinyl, especially C₃-C₆-alkinyl,hydroxyalkyl, especially C₁-C₆-hydroxyalkyl, alkoxy, especiallyC₁-C₆-alkoxy, alkenyloxy, especially C₃-C₆-alkenyloxy, alkinyloxy,especially C₃-C₆-alkinyloxy, alkanoyloxy, especially C₁-C₇-alkanoyloxy,alkoxycarbonyloxy, especially C₂-C₇-alkoxycarbonyloxy, alkylthio,especially C₁-C₆-alkylthio, alkenylthio, especially C₃-C₆-alkenylthio,alkinylthio, especially C₃-C₆-alkinylthio, cycloalkyl, especiallyC₃-C₈-cycloalkyl, cycloalkyloxy, especially C₃-C₈-cycloalkyloxy,cycloalkylthio, especially C₃-C₈-cycloalkylthio, alkoxycarbonyl,especially C₂-C₇-alkoxycarbonyl, alkylaminocarbonyl, especiallyC₂-C₇-alkylaminocarbonyl, dialkylaminocarbonyl, especiallyC₃-C₁₃-dialkylaminocarbonyl, or NR⁵R⁶, wherein R⁵ and R⁶ are selectedindependently of each other from hydrogen, alkyl, especiallyC₁-C₆-alkyl, alkenyl, especially C₃-C₆-alkenyl and alkinyl, especiallyC₃-C₆-alkinyl, R² is hydrogen, halogen, cyano, hydroxy, trifluoromethyl,benzyloxy, alkyl, especially C₁-C₆-alkyl, alkoxy, especiallyC₁-C₆-alkoxy or alkanoyloxy, especially C₁-C₇-alkanoyloxy, wherein R¹and R², if they are adjacent, optionally form a bridge which is selectedfrom—(CH₂)₄—, —(CH═CH)₂— and —CH₂O—CR⁷R⁸—O—, wherein R⁷ and R⁸ are,independently of each other, hydrogen or alkyl, especially C₁-C₆-alkyl,R³ is hydrogen, halogen, alkyl, especially C₁-C₆-alkyl, trifluoromethylor hydroxyalkyl, especially C₁-C₆-hdroxyalkyl and R⁴ is hydrogen,hydroxy, benzyloxy, alkyl, especially C₁-C₆-alkyl, alkenyl, especiallyC₃-C₆-alkenyl, alkinyl, especially C₃-C₆-alkinyl, cycloalkyl, especiallyC₃-C₆-cycloalkyl or alkoxy, especially C j-C₆-alkoxy, k is 0 or 1, A isalkenylene with at least than two C-atoms, especially C₂-C₆— alkenylene,which is optionally substituted once to threefold by C₁-C₃-alkyl,hydroxy, C₁-C₃-alkoxy, fluorine, cyano or phenyl, alkadienylene with atleast four C-atoms, especially C₄-C₆— alkadienylene, which is optionallysubstituted once or twice by C₁-C₃-alkyl, fluorine, cyano or phenyl,1,3,5-hexatrienylene, which is optionally substituted by C₁-C₃-alkyl,fluorine, cyano, or phenyl, ethinylene D is selected from alkylene,especially C₁-C₁₀-alkylene, optionally substituted once or twice byalkyl, especially C₁-C₆-alkyl, hydroxy, or alkoxy, especiallyC₁-C₆-alkoxy, alkenylene with at least two C-atoms, especiallyC₂-C₁₀-alkenylene, which is optionally substituted once or twice byalkyl, especially C₁-C₆-alkyl, hydroxy, or alkoxy, especiallyC₁-C₆-alkoxy, wherein the double bond can also be to ring E, alkinylenewith at least three C-atoms, especially C₃-C₁₀-alkinylene, optionallysubstituted once or twice by alkyl especially C₁-C₆-alkyl, hydroxy oralkoxy, especially C₁-C₆-alkoxy, and alkylene, especiallyC₁-C₁₀-alkylene, alkenylene with at least two C-atoms, especiallyC₂-C₁₀-alkenylene or alkinylene with at least three C-atoms, especiallyC₃-C₁₀-alkinylene, whereby one to three methylene units are eachisosterically replaced by O, S, NR⁹, CO, SO or SO₂ wherein R⁹ isselected from hydrogen, alkyl, especially C₁-C₆-alkyl, alkenyl,especially C₃-C₆-alkenyl, alkinyl, especially C₃-C₆-alkinyl, acyl,especially C₁-C₆-acyl or alkylsulfonyl, especially C₁-C₆-alkylsulfonyl,has the same meaning as E is selected from

wherein the heterocyclic ring can also optionally have a double bond andn and p can be, independently of one another 0, 1, 2 or 3, with theproviso that n+p≦4 and q is 2 or 3, R¹⁰ is hydrogen, alkyl, especiallyC₁-C₆-alkyl, hydroxy, hydroxymethyl, carboxy or alkoxycarbonyl with atleast two C-atoms, especially C₂-C₇-alkoxycarbonyl and R¹¹ is hydrogen,alkyl, especially C₁-C₆-alkyl or or an oxo group adjacent to thenitrogen atom, wherein R¹⁰ and R¹¹ optionally together, form an alkylenebridge with 12,3, 4 or 5 C-atoms, especially a C₁-C₃-alkylene bridgeunder formation of a bicyclic ring system, G is selected from hydrogen,G1, G2, G3, G4 and G5, wherein G1 represents the residue—(CH₂)_(r)—(CR¹³R¹⁴)_(s)—R  (G1) wherein r is an integer from 1 to 3 or0 and s is 0 or 1, R¹² is selected from hydrogen, alkyl, especiallyC₁-C₆-alkyl, alkenyl with at least three C-atoms, especiallyC₃-C₆-alkenyl, alkinyl with at least three C-atoms, especiallyC₃-C₆-alkinyl, cycloalkyl with at least three C-atoms, especiallyC₃-C₈-cycloalkyl, saturated, five to seven membered heterocycles, whichcan contain one or two hetero-atoms from the group N and/or S and/or O,benzyl or phenyl, monocyclic aromatic five or six-membered heterocycles,which can contain one to three hetero-atoms from the group N and/or Sand/or O and are either bound directly or over a methylene group,anellated bi- and tricyclic aromatic or partially hydrated carbocyclicring systems with 8 to 16 ring atoms and at least one aromatic ring,wherein the linkage can occur either over an aromatic or a hydrated ringand either directly or over a methylene group, anellated bi- andtricyclic aromatic or partially hydrated heterocyclic ring systems with8 to 16 ring atoms and at least one aromatic ring, wherein one to threering atoms can be selected from N and/or S and/or O and the linkage canoccur either over an aromatic or a hydrated ring and either directly orover a methylene group, R¹³ has the same meaning as R¹², but is selectedindependently thereof, R¹⁴ is selected from hydrogen, hydroxy, methyl,benzyl, phenyl, monocyclic aromatic five- or six-membered heterocycles,which can contain one to three hetero-atoms selected from the group Nand/or S and/or O and are either bound directly or over a methylenegroup, anellated bi- and tricyclic aromatic or partially hydratedcarbocyclic ring systems with 8 to 16 ring atoms and at least onearomatic ring, wherein the linkage can occur either over an aromatic ora hydrated ring and either directly or over a methylene group, anellatedbi- and tricyclic aromatic or partially hydrated heterocyclic ringsystems with 8 to 16 ring atoms and at least one aromatic ring, whereinone to three ring atoms can be selected from N and/or S and/or O and thelinkage can occur either over an aromatic or a hydrated ring and eitherdirectly or over a methylene group, G2 is the residue

wherein the substituents R¹² and R¹⁴ can have the above meaning or thegrouping—NR¹²R¹⁴ can also be a nitrogen heterocycle bound over the nitrogenatom, selected from saturated or unsaturated monocyclic, four- toeight-membered heterocycles, which, aside from the essential nitrogenatom, can optionally contain one or two further hetero-atoms selectedfrom the group N and/or S and/or O, or saturated or unsaturated bi- ortricyclic, anellated or bridged heterocycles with 8 to 16 ring atoms,which, aside from the essential nitrogen atom, can optionally containone or two further hetero-atoms selected from the group N and/or Sand/or O, G3 is the residue—SO₂—(CH₂)_(r)R¹²  (G3) and G4 is the residue

wherein Ar¹ and Ar² are selected independently from one another fromphenyl, pyridyl or naphthyl and G5 is the residue—COR¹⁵  (G5) wherein R¹⁵ is selected from trifluoromethyl, alkoxy,especially C₁-C₆-alkoxy, alkenyloxy, especially C₃-C₆-alkenyloxy, orbenzyloxy, wherein any aryl residues and/or aromatic ring systems in thesubstituents R¹, R², R⁴, R¹², R¹³, R¹⁴, R¹⁵, Ar¹ and Ar² and/or in thering system —NR¹²R¹⁴ can be substituted independently from each other byone to three of the same or different residues which are selected fromhalogen, cyano, alkyl, especially C₁-C₆-alkyl, trifluoromethyl,cycloalkyl, especially C₃-C₈-cycloalkyl, phenyl, benzyl, hydroxy,alkoxy, especially C₁-C₆-alkoxy, alkoxy, substituted entirely orpartially by fluorine, substituted alkoxy especially C₁-C₆-alkoxy,benzyloxy, phenoxy, mercapto, alkylthio, especially C₁-C₆-alkylthio,carboxy, alkoxycarbonyl, especially C₁-C₆-alkoxycarbonyl,benzyloxycarbonyl, nitro, amino, monoalkylamino, especially monoC₁-C₆-alkylamino, dialkylamino, especially di-(C₁-C₆-alkyl)-amino andmethylenedioxy for two adjacent groups on the aromatic ring or ringsystem, wherein each of the residues alkyl, alkenyl, alkinyl,hydroxyalkyl, alkoxy, alkenyloxy, alkinyloxy, alkanoyloxy,alkoxycarbonyl, alkoxycarbonyloxy, alkylthio, alkenylthio, alkinylthio,alkylene, acyl, alkylsulfonyl, alkenylene, alkinylene, cycloalkyl,cycloalkyloxy, alkoxycarbonyl, alkylaminocarbonyl ordialkylaminocarbonyl of the substituents R¹ to R¹³ can have 1 to 2 or 4,6, 8, 10 or 12 C-atoms and/or 2 or 3 to 5, 7, 9, 11 or 13 and/or 15C-atoms or 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 C-atoms dependingon the structure, as well as stereoisomers and/or mixtures thereof andpharmacologically acceptable acid addition salts with the exception of(E)-3-(3-piridyl)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-propenamidehydrochloride.
 2. Compound of formula (I)

wherein R¹ is a hydrogen, halogen, cyano, C₁-C₆-alkyl, C₃-C₆-alkenyl,C₃-C₆-alkinyl, trifluoromethyl, C₃-C₈-cycloalkyl, C₁-C₆-hydroxyalkyl,hydroxy, C₁-C₆-alkoxy, C₃-C₆-alkenyloxy, C₃-C₆-alkinyloxy, benzyloxy,C₁-C₇-alkanoyloxy, C₂-C₇-alkoxycarbonyloxy, C₁-C₆-alkylthio,C₃-C₆-alkenylthio, C₃-C₆-alkinylthio, C₃-C₈-cycloalkyloxy,C₃-C₈-cycloalkylthio, C₂-C₇-alkoxycarbonyl, aminocarbonyl,C₂-C₇-alkylaminocarbonyl, C₃-C₁₃-dialkylaminocarbonyl, carboxy, phenyl,phenoxy, phenylthio, pyridyloxy, pyridylthio, or NR⁵R⁶, wherein R⁵ andR⁶ are selected independently from each other from hydrogen,C₁-C₆-alkyl, C₃-C₆-alkenyl and C₃-C₆-alkinyl, R² is hydrogen, halogen,cyano, C₁-C₆-alkyl, trifluoromethyl, hydroxy, C₁-C₆-alkoxy, benzyloxy orC₁-C₇-alkanoyloxy, wherein R¹ and R², in case they are adjacent,optionally form a bridge which is selected from the bridge members—(CH₂)₄—, and —(CH═CH)₂— and —CH₂O—CR⁷R⁸—O—, wherein R⁷ and R⁸ are,independently from each other, hydrogen or C₁-C₆-alkyl, R³ is hydrogen,halogen, C₁-C₆-alkyl, trifluoromethyl or C₁-C₆-hydroxyalkyl and R⁴ ishydrogen, C₁-C₆-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkinyl, C₃-C₆-cycloalkyl,hydroxy, C₁-C₆-alkoxy or benzyloxy, k is 0 or 1, A is C₂-C₆-alkenylene,which is optionally substituted once to three-fold by C₁-C₃-alkyl,hydroxy, C₁-C₃-alkoxy, fluorine, cyano or phenyl, C₄-C₆-alkadienylene,which is optionally substituted once or twice by C₁-C₃-alkyl, fluorine,cyano or phenyl 1,3,5-hexatrienylene, which is optionally substituted byC₁-C₃-alkyl, fluorine, cyano or phenyl ethinylene D is selected fromC₁-C₁₀-alkylene, optionally substituted once or twice by C₁-C₆-alkyl,hydroxy, or C₁-C₆-alkoxy, C₂-C₁₀-alkenylene, which is optionallysubstituted once or twice by C₁-C₆-alkyl, hydroxy, or C₁-C₆-alkoxy,wherein the double bond can also be to ring E, C₃-C₁₀-alkinylene,optionally substituted once or twice by C₁-C₆-alkyl, hydroxy, orC₁-C₆-alkoxy, and C₁-C₁₀-alkylene, C₂-C₁₀-alkenylene orC₃-C₁₀-alkinylene, wherein one to three methylene units are eachisosterically replaced by O, S, NR⁹, CO, SO or SO₂, wherein R⁹ isselected from hydrogen, C₁-C₆-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkinyl,C₁-C₆-acyl or C₁-C₆-alkylsulfonyl, E is selected from

wherein the heterocyclic ring can optionally have a double bond and nand p can be, independently of each other, 0, 1, 2 or 3, with theproviso that n+p≦4 and q is 2 or 3, R¹⁰ is hydrogen, C₁-C₆-alkyl,hydroxy, hydroxymethyl, carboxy or C₂-C₇-alkoxycarbonyl and R¹¹hydrogen, C₁-C₆-alkyl or an oxo group adjacent to the nitrogen atom,wherein R¹⁰ and R¹¹ optionally together form a C₁-C₃-alkylene bridgeunder formation of a bi-cyclic ring system, G is selected from hydrogen,G1, G2, G3, G4 and G5, wherein G1 represents the residue—(CH₂)_(r)—(CR¹³R¹⁴)_(s)—R¹²   wherein r is an integer from 1 to 3 or Oand S is 0 or 1, R¹² is selected from hydrogen, C₁-C₆-alkyl,C₃-C₆-alkenyl, C₃-C₆-alkinyl, C₃-C_(g)-cycloalkyl, saturated, five- toseven-membered heterocycles, which can contain one or two hetero-atomsfrom the group N and/or S and/or O, benzyl or phenyl, monocyclicaromatic five or six-membered heterocycles, which can contain one tothree hetero-atoms from the group N and/or S and/or O and are eitherbound directly or over a methylene group, anellated bi- and tricyclicaromatic or partially hydrated carbocyclic ring systems with 8 to 16ring atoms and at least one aromatic ring, wherein the linkage can occureither over an aromatic or a hydrated ring and either directly or over amethylene group, anellated bi- and tricyclic aromatic or partiallyhydrated heterocyclic ring systems with 8 to 16 ring atoms and at leastone aromatic ring, wherein one to three ring atoms can be selected fromN and/or S and/or O and the linkage can occur either over an aromaticring or a hydrated ring and either directly or over a methylene group,R¹³ has the same meaning as R¹², but is selected independently thereof,R¹⁴ is selected from hydrogen, hydroxy, methyl, benzyl, phenyl,monocyclic aromatic five- or six-membered heterocycles, which cancontain one to three hetero-atoms selected from the group N and/or Sand/or O and are either bound directly or over a methylene group,anellated bi- and tricyclic aromatic or partially hydrated carbocyclicring systems with 8 to 16 ring atoms and at least one aromatic ring,wherein the linkage can occur either over an aromatic or a hydrated ringand either directly or over a methylene group, anellated bi- andtricyclic aromatic or partially hydrated heterocyclic ring systems with8 to 16 ring atoms and at least one aromatic ring, wherein one to threering atoms can be selected from N and/or S and/or O and the linkage canoccur either over an aromatic ring or a hydrated ring and eitherdirectly or over a methylene group, G2 is the residue

wherein the substituents R¹² and R¹⁴ can have the above meaning or thegrouping—NR¹²R¹⁴ can also be a nitrogen heterocycle bound over the nitrogenatom, selected from saturated or unsaturated monocyclic, four- toeight-membered heterocycles, which, aside from the essential nitrogenatom, can optionally contain one or two further hetero-atoms selectedfrom the group N and/or S and/or O, or saturated or unsaturated bi- ortricyclic, anellated or bridged heterocycles with 8 to 16 ring atoms,which, aside from the essential nitrogen atom, can optionally containone or two further hetero-atoms selected from the group N and/or Sand/or O, G3 is the residue—SO₂—(CH₂)_(r)R¹²  (G3) and G4 is the residue

wherein Ar¹ and Ar² are selected independently from one another fromphenyl, pyridyl or naphthyl and G5 is the residue—COR¹⁵  (G5) wherein R¹⁵ is selected from trifluoromethyl, C₁-C₆-alkoxy,C₃-C₆-alkenyloxy, or benzyloxy, and wherein aromatic ring systems in thesubstituents R¹, R², R⁴, R¹², R¹³, R¹⁴, R¹⁵, Ar¹ and Ar² and/or in thering system —NR¹²R¹⁴ can be substituted independently from each other byone to three of the same or different residues which are selected fromhalogen, cyano, C₁-C₆-alkyl, trifluoromethyl, C₃-C₈-Cycloalkyl, phenyl,benzyl, hydroxy, C₁-C₆-alkoxy, which can optionally be entirely orpartially substituted by fluorine, benzyloxy, phenoxy, mercapto,C₁-C₆-alkylthio, carboxy, C₁-C₆-alkoxycarbonyl, benzyloxycarbonyl,nitro, amino, mono-C₁-C₆-alkylamino or di-(C₁-C₆-alkyl)-amino andmethylenedioxy for two adjacent groups on the aromatic ring or ringsystem, their stereoisomers thereof and/or their mixtures thereof andpharmacologically acceptable acid addition salts with the exception of(E)-3-(3-piridyl)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2-propenamidehydrochloride.
 3. Compounds according to claim 1 or 2, characterized inthat the substituents R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹², R¹³, R¹⁴and R¹⁵ as well as A and D indicated therein have the following meaningin connection with the given substitutions according to formula (I)

wherein halogen is fluorine, chlorine, bromine or iodine, C₁-C₆-alkylcan be straight chain or branched and is preferably a methyl-, ethyl-,propyl-, isopropyl-, butyl-, isobutyl-, secbutyl-, tert-butyl-,cyclopropylmethyl-, pentyl-, isopentyl-, tert-pentyl-, neopentyl-,cyclopropylethyl-, cyclobutylmethyl- or a hexyl group, alkylene is forexample methylene, ethylene, propylene, tetramethylene, pentamethylene,hexamethylene, heptamethylene, octamethylene, nonamethylene ordecamethylene, C₃-C₆-alkenyl is straight chain or branched and ispreferably an allyl-, 2-butenyl-, 3-butenyl-, 2-methyl-2-propenyl-,2-pentenyl-, 4-pentenyl-, 2-methyl-2-butenyl-, 3-methyl-2-butenyl-,2-hexenyl-, 5-hexenyl-, 4-methyl-3-pentenyl- or 2,2-dimethyl-3-butenylgroup, alkenylene is for example ethenylene, propenylene, butenylene,pentenylene, hexenylene, hexathenylene, heptenylene, octenylene,nonenylene or decenylene, C₃-C₆-alkinyl is straight chain or branchedand is preferably a propargyl-, 2-butinyl-, 3-butinyl-, 4-pentinyl-,5-hexinyl- or 4-methyl-2-pentinyl group, alkinylene is for examplepropinylene, butinylene, pentinylene, hexinylene, heptinylene,octinylene, noninylene or decinylene, C₃-C₈-cycloalkyl is preferablycyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl, C₁-C₆-hydroxyalkyl contains a hydroxyl group in one of theabove-named C₁-C₆-alkyl residues, especially in the form of thehydroxymethyl- and hydroxyethyl group, wherein C₁-C₆-alkoxy,C₃-C₆-alkenyloxy, C₃-C₆-alkinyloxy each contain, aside from the oxygenatom, one of the C₁-C₆-alkyl-, C₃-C₆-alkenyl- and/or C₃-C₆-alkinylgroups named above and the methoxy-, ethoxy-, isopropoxy-, tert-butoxy-,allyloxy- and propargyloxy group are preferred and is to be understoodas among C₁-C₆-alkoxy entirely or partially substituted with fluorine,for example difluormethoxy, trifluormethoxy or 2,2,2-trifluorethoxy,C₁-C₆-alkylthio, C₃-C₆-alkenylthio, C₃-C₆-alkinylthio each contain,aside from the sulfur atom, one of the C₁-C₆-alkyl-, C₃-C₆-alkenyl- orC₃-C₆-alkinyl group named above, especially the methylthio-, ethylthio-,isopropylthio- and tert-butylthio group, C₃-C₈-cycloalkyloxy andC₃-C₈-cycloalkylthio are preferred as cyclopentyloxy- andcyclopentylthio- and/or cylohexyloxy- and cyclohexylthio groups,C₁-C₇-alkanoyloxy groups contain, aside from the oxygen atom, analiphatic acyl residue with 1 to 7 carbon atoms, especially theacetoxy-, propionyloxy- and pivaloyloxy group, C₂-C₇-alkoxycarbonylgroups contain, aside from the carbonyl group, one of the C₁-C₆-alkoxygroups mentioned above, especially the methoxycarbonyl-,ethoxycarbonyl-, isopropoxycarbonyl-, isobutoxycarbonyl- andtert-butoxycarbonyl group, C₂-C₇-alkoxycarbonyloxy groups contain, asidefrom the oxygen atom, one of the C₂-C₇-alkoxycarbonyl residues mentionedabove, especially the methoxycarbonyloxy-, ethoxycarbonyloxy-,isopropoxycarbonyloxy-, isobutoxycarbonyloxy- and tert-butoxycarbonylgroup as well as the allyloxycarbonyloxy group, C₂-C₇-alkylaminocarbonyland C₃-C₁₃-dialkylaminocarbonyl groups contain, beside the carbonylgroup, an alkylamino- and/or dialkylamino residue, whose C₁-C₆-alkylgroups have the above meanings, wherein the dimethylaminocarbonyl-,diethylaminocarbonyl- and the diisopropylaminocarbonyl groups arepreferred, and one of the following C₁-C₆-alkylamino groups and/ordi-(C₁-C₆-alkyl)amino groups are to be understood under the amino groupsof the formula NR⁵R⁶, aside from the unsubstituted amino group,C₁-C₆-alkylamino contains one of the C₁-C₆-alkyl groups mentioned above,especially in form of the methylamino-, ethylamino-, propylamino-,isopropylamino-, butylamino- and the tert-butylamino group,di-(C₁-C₆-alkyl)amino carries two of the same or different of the abovenamed C₁-C₆-alkyl groups on the nitrogen atom, especially in form of thedimethylamino-, diethylamino-, dipropylamino-, diisopropylamino-,isopropylmethylamino-, dibutylamino- or tert-butylmethylamino group,C₁-C₆-acyl is the residue of an aliphatic saturated or unsaturated,straight chain, branched or cyclic carboxylic acid, especially in formof the formyl-, acetyl-, propionyl-acryloyl-, butyryl-, isobutyryl-,methacryloyl-, cyclopropylcarbonyl-, pentanoyl-, pivaloyl-,cyclobutylcarbonyl-, hexanoyl- and the dimethylacryloyl group,C₁-C₆-alkansulfonyl is preferably the methanesulfonyl-, ethanesulfonyl-,propanesulfonyl-, butanesulfonyl-, pentanesulfonyl- and thehexanesulfonyl group, saturated five- to seven-membered heterocycleswith one or two hetero-atoms are especially tetrahydrofuryl,tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, Piperidinyl,hexahydroazepinyl, piperazinyl, hexahydrodiazepinyl or morpholinyl,monocyclic aromatic five- or six-membered heterocycles with one to threehetero-atoms are especially furyl, thienyl, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl,thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl ortriazinyl, anellated bi- and tricyclic aromatic or partially hydratedcarbocycle ring systems with 8 to 16 ring atoms and at least onearomatic ring are preferably benzocyclobutyl, indanyl, indenyl,naphthyl, dihydronaphthyl, tetrahydronaphthyl, biphenylenyl, fluorenyl,anthryl, dihydroanthryl, phenanthryl, dihydrophenanthryl,dibenzocycloheptenyl, dihydrodibenzocycloheptenyl,dihydrodibenzocyclooctenyl or tetrahydrodibenzocyclooctenyl, whereintheir mono- or dioxo-derivates, for example, the residues of indanone,tetralone, anthrene, anthraquinone, fluorenone, phenanthrone,dibenzocycloheptenone, dihydrodibenzocycloheptenone ortetrahydrodibenzocyclooctenone are also to be understood as partiallyhydrated carboxylic ring systems, anellated bi- and tricyclischearomatic or partially hydrated heterocyclic ring systems with 8 to 16ring atoms and at least one aromatic ring are among, for example,imidazothiazolyl, benzofuryl, dihydrobenzofuryl, benzothienyl,dihydrobenzothienyl, indolyl, indolinyl, benzimidazolyl, indazolyl,benzoxazolyl, benzisoxazolyl, benzo-thiazolyl, benzoisothiazolyl,benzofurazanyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl,thiazolopyridyl, isothiazolopyridyl, imidazopyridyl, pyrazolopyridyl,thienopyrimidinyl, chromanyl, benzopyranyl, quinolyl, isoquinolyl,dihydroquinolyl, tetrahydroquinolyl, benzodioxanyl, quinoxalinyl,quinazolinyl, naphthyridinyl, carbazolyl, tetrahydrocarbazolyl,pyridoindolyl, acridinyl, phenothiazinyl, dihydrodibenzoxepinyl,benzocycloheptathienyl, dihydrothienobenzothiepinyl,dihydrodibenzothiepinyl, octahydrodibenzothiepinyl,dihydrodibenzazepinyl, octahydrodibenzazepinyl, benzocycloheptapyridyl,dibydropyridobenzodiazepinyl, dihydrodibenzoxazepinyl,dihydropyridobenzoxepinyl, dihydropyridobenzoxazepinyl,dihydrodibenzothiazepinyl or dihydropyridobenzothiazepinyl, whereintheir mono- or dioxo-derivates and/or optionally their possibletautomeres are also to be understood as partially hydrated heterocyclicring systems, for example, the residues of indolinane, isatin,benzoxazolone and/or their tautomeres hydroxybenzoxazol, ofbenzisoxazolone, benzothiazolone, benzoisothiazolone and benzimidazoloneand/or their tautomeres, hydroxybenzisoxazol, hydroxybenzothiazol,hydroxybenzoisothiazol and hydroxybenzimidazol, of indazolinone, ofoxazolopyridinone, thiazolopyridinones, pyrazolopyridinones andimidazopyridinones and/or their tautomeres hydroxyoxazolopyridine,hydroxythiazolopyridines, hydroxypyrazolopyridines andhydroxyimidazopyridines, the residues of chromanone, chromone,quinolinone, di-hydroquinolinone, tetrahydrocarbazolone, acridone, ofdihydrodibenzoxepinones, benzocycloheptathiophenones,dihydrothienobenzothiepinones, dihydrodibenzo-thiepinones,dihydrodibenzoazepinones, benzocycloheptapyridinones,dihydropyrido-benzoxazepinones, dihydrodibenzothiazepinones and ofdihydropyridobenzothiazepi-nones, saturated and unsaturated monocyclic,four- to eight-membered heterocycles are —NR¹²R¹⁴ as a grouping which,aside from the essential nitrogen atom, can optionally contain one ortwo further hetero-atoms selected from N and/or S and/or O, for exampleazetidine, pyrrolidine, piperidine, (1H)tetrahydropyridine,hexahydroazepine, (1H)tetrahydroazepine, octahydroazocine, pyrazolidine,piperazine, hexahydrodiazepine, morpholine, hexahydrooxazepine,thiomorpholine or thiomorpholine-1,1-dioxide, saturated or unsaturatedbi- or tricyclic, anellated or bridged heterocycles with 8 to 16 ringatoms, represent —NR¹²R¹⁴ as a grouping which, aside from the essentialnitrogen atom can optionally contain one or two further hetero-atoms,selected from N and/or S and/or O, for example5-aza-bicyclo[2.1.1]hexane, 2-aza-bicyclo[2.2.1]heptane,7-aza-bicyclo[2.2.1]heptane, 2,5-diaza-bicyclo[2.2.1]heptane,2-aza-bicyclo[2.2.2]octane, 8-aza-bicyclo[3.2.1]octane,2,5-diaza-bicyclo[2.2.2]octane, 9-aza-bicyclo[3.3.1]nonane, indoline,isoindoline, (1H)-dihydroquinoline, (1H)-tetrahydroquinoline,(2H)-tetrahydroisoquinoline, (1H)-tetrahydroquinoxaline,(4H)-dihydrobenzoxazine, (4H)-dihydrobenothiazine,(1H)-tetrahydrobenzo[b]azepine, (1H)-tetrahydrobenzo[c]azepine,(1H)-tetrahydrobenzo[d]azepine, (5H)-tetrahydrobenzo[b]oxazepine,(5H)-tetrahydrobenzo[b]thiazepine,1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol, (10H)-dihydroacridine,1,2,3,4-tetrahydroacridanone, (10H)-phenoxazine, (10H)-phenothiazine,(5H)-dibenzazepine, (5H)-dihydrodibenzazepine,(5H)-octahydrodibenozepine, (5H)-dihydrodibenzodiazepine,(11H)-dihydrodibenzo[b,e]oxazepine, (11H)-dihydrodibenzo[b,e]thiazepine,(10H)-dihydro-dibenzo[b,f]oxazepine, (10H)-dihydrodibenzo[b,f]tiazepineor (5H)-tetrahydrodibenzazocine, as well as optionally typicaltautomeres in the case of substitution of the heterocycle as such or inan antellated ring system by free hydroxy-, mercapto- and/or aminogroups, and stereoisomers such as, if applicable, cis/trans-isomers,endo/exo-isomers, optic isomers such as enantiomers, diastereomers aspure isomers or mixtures and/or racemic mixtures as well as thepharmacologically acceptable acid addition salts with inorganic ororganic acids, wherein the hydrochlorides, hydrobromides, hydroiodides,sulfates and phosphates, are preferred as addition salts with suitableinorganic acids and acetates, benzoates, 4-methoxybenzoate, 2- or4-hydroxybenzoate, 4-chlorobenzoate, ascorbate, salicylate, formate,glutarate, tricarballylate, citrates, fumarates, gluconates, malates,maleates, methanesulfonates, lactates, oxalates, succinates, tartratesand tosylates, for example p-tosylate are preferred as addition salts oforganic acids.
 4. Compounds according to one of the claims 1-3,characterized in that the substitutents labelled in formula (I)

have the following meanings: R¹ is hydrogen, halogen, cyano,C₁-C₆-alkyl, trifluoromethyl, C₃-C₈-cycloalkyl, C₁-C₄-hydroxyalkyl,hydroxy, C₁-C₄-alkoxy, benzyloxy, C₁-C₄-alkanoyloxy, C₁-C₄-alkylthio,C₂-C₅-alkoxycarbonyl, aminocarbonyl, C₃-C₉-dialkylaminocarbonyl,carboxy, phenyl, phenoxy, pyridyloxy or NR⁵R⁶, wherein R⁵ and R⁶ areselected independently from each other from hydrogen and C₁-C₆-alkyl, R²is hydrogen, halogen, C₁-C₆-alkyl, trifluoromethyl or hydroxy, whereinR¹ and R², in the case they are adjacent, optionally form a bridge whichare selected from the group of bridge members —(CH₂)₄— and —(CH═CH)₂—and —CH₂O—CR⁷R⁸—O—, wherein R⁷ and R⁸ can be, independently from eachother, hydrogen and C₁-C₆-alkyl, R³ is selected from hydrogen, halogenand C₁-C₆-alkyl and R⁴ is selected from hydrogen, C₁-C₆-alkyl,C₃-C₆-alkenyl, hydroxy, C₁-C₆-alkoxy and benzyloxy, k is 0 or 3, A isC₂-C₆-alkenylene, which is optionally substituted one to three-fold byC₁-C₃-alkyl, hydroxy, fluorine, cyano, or phenyl, or isC₄-C₆-alkadienylene, which is optionally substituted once or twice byC₁-C₃-alkyl, fluorine, cyano, or phenyl, or 1,3,5-hexatrienylene, whichis optionally substituted by C₁-C₃ alkyl, fluorine, or cyano, as well asethinylene, D is selected from C₁-C₁₀-alkylene, which is optionallysubstituted once or twice by C₁-C₃-alkyl or hydroxy, as well asC₂-C₁₀-alkenylene, optionally substituted once or twice by C₁-C₃-alkylor hydroxy, wherein the double bond can also be to ring E orC₃-C₁₀-alkinylene, which is optionally substituted once or twice byC₁-C₃-alkyl or hydroxy, as well as C₁-C₁₀-alkylene, C₂-C₁₀-alkenylene orC₃-C₁₀-alkinylene, in which one to three methylene units areisosterically replaced by O, S, NR⁹, CO, SO or SO₂, wherein R⁹ ishydrogen, C₁-C₃-alkyl, C₁-C₆-acyl or methanesulfonyl,

wherein the heterocyclic ring can optionally have a double bond and nand p can be, independent of each other, 0, 1, 2 or 3, with the provisothat n+p≦4, q is 2 or 3, R¹⁰ is selected from hydrogen, C₁-C₃-alkyl,hydroxy, hydroxymethyl, carboxy or C₂-C₇-alkoxycarbonyl and R¹¹ isselected from hydrogen or an oxo group adjacent to the nitrogen atom, Gis selected from hydrogen, G1, G2, G3, G4 and G5, wherein G1 representsthe residue—(CH₂)_(r)—(CR¹³R¹⁴)_(s)—R¹²  (G1) wherein r is 0, 1 or 2 and s is 0 or1, R¹² is selected from hydrogen, C₁-C₆-alkyl, C₃-C₆-alkenyl,C₃-C₆-alkinyl, C₃-C₈-cycloalkyl, benzyl, phenyl, monocyclic aromaticfive- or six-membered heterocycles, which contain one to threehetero-atoms from the group N and/or S and/or O and are either bounddirectly or over a methylene group, anellated bi- and tricyclic aromaticor partially hydrated carbocyclic ring systems with 8 to 16 ring atomsand at least one aromatic ring, whereby the bond can occur either overan aromatic or a hydrated ring and either directly or over a methylenegroup, anellated bi- and tricyclic aromatic or partially hydratedheterocyclic ring systems with 8 to 16 ring atoms and at least onearomatic ring, wherein one to three ring atoms can be selected from thegroups N and/or S and/or O and the bond can occur either over anaromatic or a hydrated ring and either directly or over a methylenegroup, R¹³ has the same meaning as R¹², but is selected independentlythereof, R¹⁴ is selected from hydrogen, hydroxy, methyl, benzyl orphenyl, monocyclic aromatic five- or six-membered heterocycles, whichcan contain one to three hetero-atoms selected tfom the group N and/or Sand/or O and are bound either directly or over a methylene group,anellated bi- and tricyclic aromatic or partially hydrated carbocyclicring systems with 8 to 16 ring atoms and at least einen aromatic ring,wherein the bond can occur either over an aromatic or a hydrated ringand either directly or over a methylene group, anellated bi- andtricyclic aromatic or partially hydrated heterocyclic ring systems with8 to 16 ring atoms and at least one aromatic ring, wherein one to threering atoms can be selected from the group N and/or S and/or O and thebond can occur either over an aromatic or a hydrated ring and eitherdirectly or over a methylene group, G2 is selected from the residues

wherein the substituents R¹² and R¹⁴ can have the above meaning, or thegrouping—NR¹²R¹⁴ can also be a nitrogen heterocycle bound over the nitrogenatom, selected from saturated or unsaturated monocyclic, four- toeight-membered heterocycles, which, aside from the essential nitrogenatom, can optionally contain one or two further hetero-atoms selectedfrom N and/or S and/or O, or saturated or unsaturated bi- or tricyclic,anellated or bridged heterocycles with 8 to 16 ring atoms, which, asidefrom the essential nitrogen atom, can optionally contain one or twofurther hetero-atoms selected from N and/or S and/or O, G3 is theresidue—SO₂—(CH₂)_(r)R¹²  (G3), G4 is the residue

wherein Ar¹ and ArZ are selected independently of each other fromphenyl, pyridyl or naphthyl, G5 is the residue—COR¹⁵  (G5) wherein R¹⁵ is trifluoromethyl, C₁-C₆-alkoxy,C₃-C₆-alkenyloxy or benzyloxy and aromatic ring systems in which thesubstituents R¹, R², R⁴, R¹², R¹³, R¹⁴, R¹⁵, Ar¹ and Ar² and/or in thering system —NR¹²R¹⁴ can carry independently of each other one to threeof the same or different substituents from the series halogen, cyano,C₁-C₆-alkyl, trifluoromethyl, C₃-C₈-cycloalkyl, phenyl, benzyl, hydroxy,C₁-C₆-alkoxy, which is optionally entirely or partially substituted byfluorine, benzyloxy, phenoxy, mercapto, C₁-C₆-alkylthio, carboxy,C₁-C₆-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino,mono-C₁-C₆-alkylamino, di-(C₁-C₆-alkyl)-amino, wherein two adjacentgroups on the aromatic ring or ring system can form an additional ringover a methylenedioxy bridge.
 5. Compounds according to one of theclaims 1-4, characterized in that the substitutents labelled in formula(I)

have the following meanings: R¹ is hydrogen, halogen, cyano, methyl,trifluoromethyl, hydroxy, C₁-C₄-alkoxy, ethylthio, methoxycarbonyl,tert-butoxycarbonyl, aminocarbonyl, carboxy, and phenoxy, R² ishydrogen, halogen, trifluoromethyl or hydroxy, R³ is hydrogen orhalogen, R⁴ is selected from hydrogen, C₁-C₃-alkyl, hydroxy andC₁-C₃-alkoxy, k is 0 or 1, A is C₂-C₆-alkenylene, which is optionallysubstituted once or twice by C₁-C₃-alkyl, hydroxy or fluorine,C₄-C₆-alkadienylene, which is optionally substituted by is C₁-C₃-alkylor by 1 or 2 fluorine atoms, 1,3,5-hexatrienylene, which is optionallysubstituted by fluorine, or C₂-C₆-alkylene, wherein a methylene unit canbe isosterically replaced by O, S, CO or SO₂, and the isostericsubstitute, with the exception of ═CO cannot be adjacent to the amidegroup and,

D is C₁-C₈-alkylene, which is optionally substituted once twice bymethyl or hydroxy, C₂-C₈-alkenylene, which is optionally substitutedonce or twice by methyl or hydroxy, wherein the double bond can also beto ring E, C₃-C₈-alkinylene, which is optionally substituted once ortwice by methyl or hydroxy, as well as C₁-C₈-alkylene, C₂-C₈-alkenyleneor C₃-C₈-alkinylene, in which one to three methylene units areisosterically replaced by O, S, NH, N(CH₃), N(COCH₃), N(SO₂CH₃), CO, SOor SO₂, E is

wherein the heterocyclic ring can optionally have a double bond and nand p can be, independent of each other, 01, 2 or 3, with the provisothat n+p≦3, q is 2 or 3, R¹⁰ is selected from hydrogen, C₁-C₃-alkyl,hydroxy, hydroxymethyl and R¹¹ is selected from hydrogen or an oxo groupwhich is adjacent to the nitrogen atom, G is hydrogen or G1, G2, G3, G4and G5, wherein G1 represents the residue—(CH₂)_(r)—(CR¹³R¹⁴)_(s)—R¹²  (G1) wherein r is 0, 1 or 2 and s is 0 or1, R¹² is selected from hydrogen, C₁-C₆-alkyl, C₃-C₈-cycloalkyl, benzylor phenyl, benzocyclobutyl, indanyl, indenyl, oxoindanyl, naphthyl,dihydronaphthyl, tetrahydronaphthyl, oxotetrahydronaphthyl,biphenylenyl, fluorenyl, oxofluorenyl, anthryl, dihydroanthryl,oxodihydroanthryl, dioxodihydroanthfyl, phenanthryl, dihydrophenanthryl,dxodihydrophenanthryl, dibenzocycloheptenyl, oxodibenzocycloheptenyl,dihydrodibenzocycloheptenyl, oxodihydrodibenzocycloheptenyl,dihydrodibenzocyclooctenyl, tetra-hydrodibenzocyclooctenyl andoxotetrahydrodibenzocyclooctenyl bound directly or over a methylenegroup, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl,imidazothiazolyl, benzofuryl, dihydrobenzofuryl, benzothienyl,dihydrobenzothienyl, indolyl, indolinyl, oxoindolinyl, dioxoindolinyl,benzoxazolyl, oxobenzoxazolinyl, benzisoxazolyl, oxobenzisoxazolinyl,benzothiazolyl, oxobenzthiazolinyl, benzoisothiazolyl,oxobenzoisothiazolinyl, benzimidazolyl, oxobenzimidazolinyl, indazolyl,oxoindazolinyl, benzofurazanyl, benzothiadiazolyl, benzotriazolyl,oxazolopyridyl, oxodihydrooxazolopyridyl, thiazolopyridyl,oxodihydrothiazolopyridyl, isothiazolopyridyl, imidazopyridyl,oxodihydroimidazopyridyl, pyrazolopyridyl, oxodihydropyrazolopyridyl,thienopyrimidinyl, chromanyl, chromanonyl, benzopyranyl, chromonyl,quinolyl, isoquinolyl, dihydroquinolyl, oxodihydroquinolinyl,tetrahydroquinolyl, oxotetrahydroquinolinyl, benzodioxanyl,quinoxalinyl, quinazolinyl, naphthyridinyl, carbazolyl,tetrahydrocarbazolyl, oxotetrahydrocarbazolyl, pyridoindolyl, acridinyl,oxodihydroacridinyl, phenothiazinyl, dihydrodibenzoxepinyl,oxodihydrodibenzoxepinyl, benzocycloheptathienyl,oxobenzocycloheptathienyl, dihydrothienobenzo-thiepinyl,oxodihydrothienobenzothiepinyl dihydrodibenzothiepinyl,oxodihydrodibenzothiepinyl, octahydrodibenzothiepinyl,dihydrodibenzazepinyl, oxodihydrodibenzazepinyl,octahydrodibenzazepinyl, benzocycloheptapyridyl,oxobenzocycloheptapyridyl, dihydropyrido-benzodiazepinyl,dihydrodibenzoxazepinyl, dihydropyridobenzoxepinyl,dihydropyridobenzoxazepinyl, oxodihydropyridobenzoxazepinyl,dihydrodibenzothiazepinyl, oxodibydrodibenzothiazepinyl,dihydropyridobenzothiazepinyl, oxodihydropyridobenzothiazepinyl, bounddirectly or over a methylene group, R¹³ has the same meaning as R¹², butis selected independently therefrom, R¹⁴ is selected from hydrogen,hydroxy, methyl, benzyl or phenyl, indanyl, indenyl, naphthyl,dihydronaphthyl, tetrahydronaphthyl, furyl, thienyl, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidipyl,triazinyl, benzofuryl, benzothienyl, indolyl, indolinyl, benzoxazolyl,benzothiazolyl, benzimidazdlyl, chromanyl, quinolyl ortetrahydroquinolyl bound directly or over a methylene group, G2 isselected from the residues

wherein the substituents R¹² and R¹⁴ can have the above meanings, orrepresents the grouping—NR¹²R¹⁴ each over the nitrogen-bound ring atom of azetidine,pyrrolidine, piperidine, (1H)tetrahydropyridine, hexahydroazepine,(1H)tetrahydroazepine, octahydroazocine, pyrazolidine, piperazine,hexyhydrodiazepine, morpholine, hexahydrooxazepine, thiomorpholine,thiomorpholine-1,1-dioxide, 5-aza-bi-cyclo[2.1.1]hexane,2-aza-bicyclo[2.2.1]heptane, 7-aza-bicyclo[2.2.1]heptane,2,5-diaza-bicyclo[2.2.1]heptane, 2-aza-bicyclo[2.2.2]octane,8-aza-bicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.2]octane,9-azabicyclo[3.3.1]nonane, indoline, isoindoline, (1H)-dihydroquinoline,(1H)-tetrahydroquinoline, (2H)-tetrahydroisoquinoline,(1H)-tetrahydroquinoxaline, (4H)-dihydrobenzoxazine,(4H)-dihydrobenzothiazine, (1H)-tetrahydrobenzo[b]azepine,(1H)-tetrahydro-benzo[c]azepine, (1H)-tetrahydrobenzo[d]azepine,(5H)-tetrahydrobenzo[b]oxazepine, (5H)-tetrahydrobenzo[b]thiazepine,1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole, (10H)-dihydroacridine,1,2,3,4-tetrahydroacridanone, (10)-phenoxazine, (10H)-phenothiazine,(5H)-dibenzazepine, (5H)-dihydrodibenzazepine,(5H)-Octahydrodibenzazepine, (5H)-dihydrodibenzodiazepine,(11H)-dihydrodibenzo[b,e]oxazepine, (1H)-dihydrodibenzo[b,e]thiazepine,(10H)-dihydrodibenzo[b,f]oxazepine, (10H)-dihydrodibenzo[b,f]thiazepineor (5H)-tetrahydrodibenzazocine, G3 is the residue—SO₂—(CH₂)_(r)R¹²  (G3), G4 is the residue

wherein Ar¹ and Ar² are selected independently of each other fromphenyl, pyridyl or naphthyl, G5 is the residue—COR¹⁵  (G5) wherein R¹⁵ is trifluoromethyl, C₁-C₆-alkoxy,C₃-C₆-alkenyloxy or benzyloxy and aromatic ring systems in which thesubstituents can be substituted independently of each other by one tothree of the same or different substituents from the series halogen,cyano, C₁-C₆-alkyl, trifluoromethyl, C₃-C₉-Cycloalkyl, phenyl, benzyl,hydroxy, C₁-C₆-alkoxy, C₁-C₆-alkoxy, which can be entirely or partiallysubstituted by fluorine, can carry benzyloxy, phenoxy, mercapto,C₁-C₆-alkylthio, carboxy, C₁-C₆-alkoxycarbonyl, benzyloxycarbonyl,nitro, amino, mono-C₁-C₆-alkylamino, di-(C₁-C₆-alkyl)-amino, wherein twoadjacent groups in the ring or ring system can form an additional ringover a methylenedioxy bridge.
 6. Compounds according to one of theclaims 1-5, characterized in that that the substituents labelled informula (I)

have the following meaning: R¹ is hydrogen, halogen, cyano, methyl,trifluoromethyl, hydroxy, methoxy or methoxycarbonyl, R² is hydrogen orhalogen, R³ is hydrogen, R⁴ is selected from hydrogen, C₁-C₃-alkyl orhydroxy, k is 0 or 1, A is C₂-C₆-alkenylene, which is optionallysubstituted once or twice by hydroxy or fluorine, or isC₄-C₆-alkadienylene, which is optionally substituted by one or twofluorine atoms, or is 1,3,5-hexatrienylene D is C₂-C₈-alkylene, which isoptionally substituted by methyl or hydroxy C₂-C₈-alkenylene, which isoptionally substituted by methyl or hydroxy, wherein the double bond canalso be to ring E, or C₂-C₈-alkylene, C₂-C₈-alkenylene, wherein one tothree methylene units are isosterically replaced by O, NH, N(CH₃),N(COCH₃), N(SO₂CH₃) or CO, E is selected from the residues

wherein the heterocyclic ring can optionally have a double bond and nand p can be, independent of each other, 0, 1, 2 or 3, with the provisothat n+p≦3 and q is 2 R¹⁰ is hydrogen, methyl or hydroxyl and R¹¹ ishydrogen or an oxo group adjacent to the nitrogen atom, G is selectedfrom hydrogen, C₃-C₈-cycloalkyl, methoxycarbonyl, tert-butoxycarbonyl,benzyloxycarbonyl, trifluoracetyl, diphenylphosphinoyl or the residues

wherein r is 0 to 2 and s is 0 or 1, R¹² is hydrogen, methyl, benzyl orphenyl, indanyl, indenyl, oxoindanyl, naphthyl, dihydronaphthyl,tetrahydronaphthyl, oxotetrahydronaphthyl, fluorineenyl, oxofluorenyl,anthryl, dihydroanthryl, oxodihydroanthryl, dioxodihydroanthryl,dibenzocycloheptenyl, oxodibenzocycloheptenyl,dihydrodibenzocycloheptenyl, oxodihydrodibenzocycloheptenyl bounddirectly or over a methylene group, furyl, thienyl, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl,imidazothiazolyl, benzofuryl, dihydrobenzofuryl, benzothienyl,dihydrobenzothienyl, indolyl, indolinyl, oxoindolinyl, dioxoindolinyl,benzoxazolyl, oxobenzoxazolinyl, benzisoxazolyl, oxobenzisoxazolinyl,benzothiazolyl, oxobenzthiazolinyl, benzoisothiazolyl,oxobenzoisothiazolinyl, benzimidazolyl, oxobenzimidazolinyl,benzofurazanyl, benzothiadiazolyl, benzotriazolyl, oxazolopyridyl,oxodihydrooxazolopyridyl, thiazolopyridyl, oxodihydrothiaolopyridyl,isothiazolopyridyl, imidazopyridyl, oxodihydroimidazopyridyl,pyrazolopyridyl, thienopyrimidinyl, chromanyl, chromanonyl,benzopyranyl, chromonyl, quinolyl, isoquinolyl, dihydroquinolyl,oxodihydroquinolinyl, tetrahydroquinolyl, oxotetrahydroquinolinyl,benzodioxanyl, quinoxalinyl, quinazolinyl, naphthyridinyl, carbazolyl,tetrahydrocarbazolyl, oxotetrahydrocarbazolyl, pyridoindolyl, acridinyl,oxodihydroacridinyl, phenothiazinyl, dihydrodibenzoxepinyl,benzocycloheptathienyl, oxobenzocycloheptathienyl,dihydrothienobenzothiepinyl, oxodihydrothienobenzothiepinyldihydrodibenzothiepinyl, oxodihydrodibenzothiepinyl,dihydrodibenzazepinyl, oxodihydrodibenzazepinyl,octahydrodibenzazepinyl, benzocycloheptapyridyl,oxobenzocycloheptapyridyl, dihydropyridobenzoxepinyl,dihydrodibenzothiazepinyl, oxodihydrodibenzothiazepinyl bound directlyor over a methylene group, R¹³ is hydrogen, methyl, benzyl or phenyl,R¹⁴ (selected from hydrogen, hydroxy, methyl, benzyl, phenyl, naphthyl,furyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyridyl, benzofuryl, benzothienyl, indolyl, indolinyl,benzoxazolyl, benzothiazolyl, benzimidazolyl, chromanyl, quinolyl ortetrahydroquinolyl, bound directly or over a methylene group, wherein informula (I)

—NR¹²R¹⁴ can also be selected from pyrrolidine, piperidine,(1H)tetrahydropyridine, hexahydroazepine, Octahydroazocine, piperazine,hexahydrodiazepine, morpholine, hexahydrooxazepine,2-azabicyclo[2.2.1]heptane, 7-azabicyclo[2.2.1]heptane,2,5-diazabicyclo[2.2.1]heptane, 8-azabicyclo[3.2.1]octane,2,5-diazabicyclo[2.2.2]octane, indoline, isoindoline,(1H)-dihydroquinoline, (1H)-tetrahydroquinoline,(2H)-tetrahydroisoquinoline, (1H)-tetrahydroquinoxaline,(4H)-dihydrobenzoxazine, (4H)-dihydrobenzothiazine,(1H)-tetrahydrobenzo[b]azepine, (1H)-tetrahydrobenzo[d]azepine,(5H)-tetrahydrobenzo[b]oxazepine, (5H)-tetrahydrobenzo[b]thiazepine,1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol, (10H)dihydroacridine,1,2,3,4-tetrahydroacridanone, (5H)-dihydrodibenzazepine,(5H)-dihydrodibenzodiazepine, (11H)-dihydrodibenzo[b,e]oxazepine,(11H)-dihydrodibenzo[b,e]thiazepine, (10H)-dihydrodibenzo[b,f]oxaze-pineor (5H)tetrahydrodibenzazocine.
 7. Compounds according to one of theclaims 1-6, characterized in that the substituents labelled in theformula (I)

have the following meanings: R¹ is hydrogen, fluorine, chlorine,bromine, methyl, trifluoromethyl or hydroxy, R² and R³ are hydrogen, R⁴is hydrogen or hydroxy, k is 0 or 1, A is C₂-C₄-alkylene, which isoptionally substituted by fluorine, D is selected from C₂-C₆-alkylene,C₂-C₆-alkenylene, wherein the double bond can also be to ring E, andC₂-C₆-alkylene and C₂-C₆-alkenylene, wherein a methylene unit isisosterically replaced by O, NH, N(CH₃) or CO or an ethylene group isisosterically replaced by NH—CO and/or CO—NH or a propylene group can beisosterically replaced by NH—CO—O and/or O—CO—NH, E is selected frompyrrolidine, piperidine, 1,2,5,6-tetrahydropyridine, hexahydroazepine,morpholine and hexahydro-1,4-oxazepine, wherein the heterocyclic ringoptionally adjacent to the nitrogen atom can be substituted by an oxogroup, G is selected from hydrogen, tert-butoxycarbonyl,diphenylphosphinoyl, or one of the residues

wherein r is 0 or 1 and S is 0 or 1, R¹² is hydrogen, methyl, benzyl orphenyl, indenyl, oxoindanyl, naphthyl, tetrahydronaphthyl, fluorenyl,oxofluorenyl, anthryl, dihydroanthryl, oxodihydroanthryl,dioxodihydroanthryl, dibenzocycloheptenyl, dihydrodibenzocycloheptenylbound directly or over a methylene group, furyl, thienyl, oxazolyl,thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl,pyrimidinyl, imidazothiazolyl, benzofuryl, benzothienyl, indolyl,oxoindolinyl, dioxoindolinyl, benzoxazolyl, oxobenzoxazolinyl,benzothiazolyl, oxobenzthiazolinyl, benzimidazolyl, oxobenzimidazolinyl,benzofurazanyl, benzotriazolyl, oxazolopyridyl,oxodihydrooxazolopyridyl, thiazolopyridyl, oxodihydrothiazolopyridyl,chromanyl, chromanonyl, benzopyranyl, chromonyl, quinolyl, isoquinolyl,oxodihydroquinolinyl, tetrahydroquinolyl, oxotetrahydroquinolinyl,benzodioxanyl, quinazolinyl, acridinyl, oxodihydroacridinyl,phenothiazinyl, dihydrodibenzoxepinyl, benzocycloheptathienyl,dihydrothienobenzothiepinyl, dihydrodibenzothiepinyl,oxodihydrodibenzothiepinyl, dihydrodibenzazepinyl,oxodihydrodibenzazepinyl, octahydrodibenzazepinyl,benzocycloheptapyridyl, oxobenzocycloheptapyridyl,dihydrodibenzothiazepinyl bound directly or over a methylene group, R¹³is hydrogen, methyl, benzyl or phenyl, R¹⁴ is hydrogen, hydroxy, methyl,benzyl or phenyl, naphthyl, furyl, thienyl, pyridyl, benzofuryl,benzothienyl, indolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl,chromanyl, quinolyl or tetrahydroquinolyl bound directly or over amethylene group, wherein in the formula

—NR¹²R¹⁴ can be selected from pyrrolidine, piperidine, hexahydroazepine,morpholine, 2,5-diazabicyclo[2.2.1]heptane, indoline, isoindoline,(1H)-dihydroquinoline, (1H)-tetrahydroquinoline,(2H)-tetrahydroisoquinoline, (1H)-tetrahydrobenzo[b]azepine,(1H)-tetrahydrobenzo[d]azepine, (5H)-tetrahydro-benzo[b]oxazepine,(5H)-tetrahydrobenzo[b]thiazepine, 1,2,3,4-tetrahydroacridanone,(5H)-dihydrodibenzazepine, (11H)-dihydrodibenzo[b,e]-oxazepine or(11H)-dihydrodibenzo[b,e]thiazepine and wherein aromatic ring systems inthe substituents can be substituted, independently of each other, by oneto three of the same or different substituents from the series halogen,cyano, C₁-C₆-alkyl, trifluoromethyl, C₃-C₈-cycloalkyl, phenyl, benzyl,hydroxy, C₁-C₆-alkoxy, C₁-C₆-alkoxy, which can be entirely or partiallysubstituted by fluorine, can carry benzyloxy, phenoxy, mercapto,C₁-C₆-alkylthio, carboxy, C₁-C₆-alkoxycarbonyl, benzyloxycarbonyl,nitro, amino, mono-C₁-C₆-alkylamino or di-(C₁-C₆-alkyl)-amino, wherebytwo adjacent groups on the aromatic ring or ring system can form anadditional ring over a methylenedioxy bridge.
 8. Compounds according toone of the claims 1-7, characterized in that the substituents labelledin the formula (I)

have the following meanings: R¹ is hydrogen, fluorine, methyl,trifluoromethyl or hydroxy, R² and R³ are hydrogen, R⁴ is hydrogen orhydroxy, k is 0, A ethenylene(vinylene) or 1,3-butadienylene D isselected from C₂-C₆-alkylene or C₂-C₆-alkenylene, wherein the doublebond can also be to ring E, E is selected from pyrrolidine, piperidine,hexahydroazepine or morpholine, G is selected from benzyl, phenethyl,fluorenylmethyl, anthrylmethyl, diphenylmethyl, fluorenyl ordihydrodibenzocycloheptenyl, furylmethyl, thienylmethyl,thiazolylmethyl, pyridylmethyl, benzothienylmethyl, quinolylmethyl,phenyl-thienylmethyl, phenyl-pyridylmethyl, dihydrodibenzoxepinyl,dihydrodibenzothiepinyl, acetyl, pivaloyl, phenylacetyl, diphenylacetyl,diphenylpropionyl, naphthylacetyl, benzoyl, naphthoyl, anthrylcarbonyl,oxofluorenylcarbonyl, oxodihydro-anthrylcarbonyl ordioxodihydroanthrylcarbonyl, furoyl, pyridylcarbonyl, chromonylcarbonyl,quinolylcarbonyl, naphthylaminocarbonyl, dibenzylaminocarbonyl,benzylphenylaminocarbonyl, diphenylaminocarbonyl, indolinyl-1-carbonyl,dihydrodibenzazepin-N-carbonyl, tetrahydroquinolinyl-N-carbonyl,tetrahydrobenzo[b]azepinyl-N-carbonyl, methanesulfonyl, phenylsulfonyl,p-toluenesulfonyl, naphthylsulfonyl, quinolinsulfonyl anddiphenylphosphinoyl, wherein aromatic ring systems can be substitutedindependently of each other by one to three of the same or differentsubstituents from the series halogen, cyano, C₁-C₆-alkyl,trifluoromethyl, C₃-C₈-cycloalkyl, phenyl, benzyl, hydroxy,C₁-C₆-alkoxy, C₁-C₆-alkoxy, which can be entirely or partiallysubstituted by fluorine, benzyloxy, phenoxy, mercapto, C₁-C₆-alkylthio,carboxy, C₁-C₆-alkoxycarbonyl, benzyloxycarbonyl, nitro, amino,mono-C₁-C₆-alkylamino or di-(C₁-C₆-alkyl)-amino, wherein two adjacentgroups in the ring or ring system can form an additional ring over amethylendioxy bridge.
 9. Compound according to one of the claims 1-8,characterized in that it is present in the form ofN-[4-(1-methylsulfonylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide,N-{4-[1-(1-(2-naphthylsulfonyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide,N-{4-[1-(2-naphthylsulfonyl)-piperidin-4-yl]-butyl}-5-(pyridin-3-yl)-2,4-pentadienoicacid amide,N-{4-[1-(1-naphthylaminocarbonyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide,N-[4-(1-diphenylaminocarbonyl-piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide,N-[4-(1-diphenylaminocarbonyl-piperidin-4-yl)-butyl]-5-(pyridin-3-yl)-2,4-pentadienoicacid amide,N-{4-[1-(10,11-dihydrodibenzo[b,f]azepin-5-yl-carbonyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamideorN-[4-(1-diphenylphosphinoyl-piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamideand/or as a pharmaceutically acceptable acid addition salt thereof. 10.Compound according to any one of the claims 1-8, characterized in thatit is present in the form ofN-[4-(1-acetylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide,N-[4-(1-diphenylacetyl-piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide,N-{4-[1-(3,3-diphenylpropionyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide,N-[4-(1-benzoylpiperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide,N-[4-(1-benzoylpiperidin-4-yl)-butyl]-5-(pyridin-3-yl)-2,4-pentadienoicacid amide, orN-{4-[1-(9-oxo-9H-fluoro-4-yl-carbonyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamideand/or as a pharmaceutically acceptable acid addition salt thereof. 11.Compound according to any one of the claims 1-8, characterized in thatit is present in the form ofN-{4-[1-(phenylpyridin-3-yl-methyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide,N-{4-[1-(phenylpyridin-4-yl-methyl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide,N-{4-[1-(6,11-dihydrodibenzo[b,e]oxepin-11-yl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamide,orN-{4-[1-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)-piperidin-4-yl]-butyl}-3-(pyridin-3-yl)-acrylamideand/or as a pharmaceutically acceptable acid addition salt thereof. 12.Compound according to any one of the claims 1-8, characterized in thatit is present in the form ofN-[7-(1-diphenylmethylpiperidin-4-yl)-heptyl]-3-(pyridin-3-yl)-acrylamide,N-[8-(1-diphenylmethylpiperidin-4-yl)-octyl]-3-(pyridin-3-yl)-acrylamide,N-[3-(1-diphenylmethylpiperidin-4-yloxy)-propyl]-3-(pyridin-3-yl)-acrylamide,or N-[3-(1-benzylpiperidin-4-yloxy)-propyl-3-(pyridin-3-yl)-acrylamideand/or as a pharmaceutically acceptable acid addition salt thereof. 13.Compound according to any one of the claims 1-8, characterized in thatit is present in the farm ofN-[2-(1-diphenylmethylpiperidin-4-yl)-ethyl]-5-(pyridin-3-yl)-2,4-pentadienoicacid amide,N-[4-(]-diphenylmethylpiperidin-4-yl)-butyl]-5-(pyridin-3-yl)-2,4-pentadienoicacid amide,N-[5-(1-diphenylmethylpiperidin-4-yl)-pentyl]-5-(pyridin-3-yl)-2,4-pentadienoicacid amide orN-[6-(1-diphenylmethypiperidin-4-yl)-hexyl]-5-(pyridin-3-yl)-2,4-pentadienoicacid amide and/or as a pharmaceutically acceptable acid addition saltthereof.
 14. Method for the production of compounds according to formula(I) according to one of the claims 1-13 characterized in that either (a)carboxylic acids of formula (II)

in which R¹, R², R³, A and k have the meaning given above or theirreactive derivatives are reacted with compounds of formula (III)

wherein D, E, G and R⁴ have the meanings given in claims 1-8 or (b)compounds of formula (I), wherein G is hydrogen, are reacted with acompound of formula (IV),L-G  (IV) in which C has the meaning given in claims 1-8, with theexception of hydrogen, and L represents a suitable nucleofuge orreactive group, whereby the type of specific nucleofuge or reactivegroup L as well as the reaction conditions are dependent on the natureof the residue G. or (c) compounds of formula (I), in which G has themeaning of G1 according to claims 1-7, with the exception of hydrogen,are produced in a such a manner that compounds of formula (I), in whichG is hydrogen, are reacted with a suitable alkylation agent and/orarylation agent of formula (IV) according to the above variant (b),wherein G is an alkyl-, alkenyl-, alkinyl-, cycloalkyl-, aryl-,aralkyl-, heteroaryl- or heteroaralkyl residue according to definitionand the nucleofuge L can be a reactive derivative of an alkohol, forexample, a halogen atom such as chlorine, bromine or iodine or asulfonic acid ester, i.e. for example a methanesulfonyloxy-,trifluoromethanesulfonyloxy-, ethanesulfonyloxy-, benzenesulfonyloxy-,p-toluenesulfonyloxy-, p-bromobenzenesulfonyloxy- orm-nitrobenzenesulfonyloxy residue, etc. or a reactive group L can be anepoxide group, I (d) compounds of formula (I), in which G represents anacyl, carbamoyl, sulfonyl or a phosphinoyl residue according to theabove definition are produced in such a manner that compounds of formula(I), in which G is hydrogen, are reacted with a carboxylic, carbamic,sulfonic and/or phosphinic acid of formula (V),HO-G  (V) wherein G is an acyl, carbamoyl, sulfonyl or phosphinoylresidue according to definition, or with derivatives thereof capable ofreaction, whereby symmetric or unsymmetric carboxylic acid anhydridesand/or sulfonic acid anhydrides or acyl- and/or sulfonyl halides,especially acyl- and/or sulfonyl chlorides and carbamoyl halides and/orphosphinic acids are used as preferred derivatives of carboxylic acidsand/or sulfonic acids (V) capable of reaction, and the reaction of theacids (V) and/or their reactive derivatives with the compounds (I), inwhich G is hydrogen, preferably occurs in the presence of auxiliarybases in solvents and under conditions as they are described in variant(a), or (e) compounds of formula (I), in which G represents a carbamoylresidue according to the definition (G2b) in the form of the grouping

wherein r=0 are produced in such a manner that compounds of formula (I),in which G is hydrogen are reacted with a carbonyl group transmitter toan intermediate product and the latter, without its purification orprevious isolation, is brought to reaction with a primary or secondaryamine with the formula (VI)H—NR¹²R¹⁴  (V) wherein R¹² and R¹⁴ and/or the grouping —NR¹²R⁴ have themeanings according to claims 1-7, wherein bis-(trichloromethyl)carbonate (triphosgene) and carbonyldiimidazol are used as particularlyreactive carbonyl group transmitters and the reaction of compounds offormula (I), wherein G is hydrogen, with triphosgene and/orcarbonyldiimidazol is preferably carried out in an absolute, inertsolvent in the presence of a tertiary organic amine as an auxiliary basein such a manner that the solution of compounds (I) and the auxiliarybase are slowly added to a solution of an equivalent amount of carbonylgroup transmitter, or (f) compounds of formula (I), in which G is acarbamoyl residue according to the definition G2, with r=0 andR¹⁴=hydrogen, with grouping

are produced in such a manner that compounds of formula (I), in which Gis hydrogen, are brought into reaction with an isocyanate of the formula(VII)O═C═N—R¹²  (VII). in which R¹² has the meaning as given in claims 1-7,wherein the reaction of the compounds of formula (I), in which G ishydrogen, with the isocyanates of formula (VII) preferably occurs in anabsolute, inert solvent, such as for example, a hydrocarbon such aspentane, hexane, heptane, benzene, toluene, or xylene, chlorinatedhydrocarbons (such as dichloromethane, chloroform, 1,2-dichloroethane,trichloroethylene), ethers (for example, diethyl ether, tetrahydrofuran,dioxane), esters such as ethyl acetate, butyl acetate, or polar aproticsolvents such as formamide or dimethylformamide and/or mixtures thereofand the reaction temperatures can lie in the region from −20° C. to 150°C., but can preferably vary from 20° C. to 100° C., or (g) compounds offormula (I), in which R⁴ is an alkyl, alkenyl, alkinyl or cycloalkylresidue according to the above definition are produced in such a mannerthat compounds of the formula (X), in which R⁴ is hydrogen, are reactedwith a suitable alkylation agent of formula (VIII)L-R⁴  (VIII) in which R⁴ is an alkyl, alkenyl, alkinyl or cycloalkylresidue according to definition and L represents a suitable nucleofuge,i.e. for example a halogen atom such as chlorine, bromine or iodine or asulfonic acid ester of an alcohol, wherein sulfonic acid esters offormula (VM) especially contain a methylsulfonyloxy group,trifluoromethanesulfonyloxy-, p-toluenesulfonyloxy-,p-bromobenzenesulfonyloxy- or m-nitrobenzenesulfonyloxy group as anucleotype L and the amide alkylation is carried out in the presence oftertiary amino groups under the use of strong auxiliary bases such aspotassium tert-butylate, sodium hydride, potassium hydride or butyllithium in aprotic, inert solvents, for example, aliphatic or aromatichydrocarbons such as pentane, hexane, heptane, benzene, toluene orethers such as tetrahydrofuran, dioxane, or poral solvents such asdimethylsulfoxide, dimethylformamide, N-methylpyrrolidone, wherein thereaction temperature can lie between 40° C. and 140° C., preferablybetween −20° C. and 80° C., depending on the reactivity of the educts.15. Method according to claim 14, characterized in that as reactivederivatives of compound (II) their activated esters, anhydrides, acidhalides, (especially acid chlorides), simple low alkyl esters,especially the p-nitrophenyl esters 2,4,6-trichlorophenyl esters,pentachlorophenyl esters, cyanomethyl esters, esters ofN-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazol,N-hydroxypiperidine, 2-hydroxypyridine or 2-mercaptopyridine are usedaccording to method variant (a), wherein symmetric as well as mixedanhydrides or for example those from the reaction with pivolyl chlorideor with chloroformates, for example, aromatic chloroformates such aschloroformic acid phenyl ester, araliphatic chloroformates such aschloroformic acid benzyl ester or aliphatic chloroformates such aschloroformic acid methyl ester, ethyl ester or isobutyl ester are usedas anhydrides, and the reaction of the compounds (II) with the compounds(III) can be facultatively preformed in the presence of condensationagents such as dicyclohexylcarbodimide,1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride,N,N-carbonyldiimidazol or1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, wherein in the case ofcarbodiimides as a condensation agent, especially N-hydroxysuccinimide,N-hydroxyphthalimide, 1-hydroxybenzotriazol or N-hydroxypiperidine canbe added, and the compounds of formula (III) as free bases as well as inform of their acid addition salts can be brought to reaction, especiallyin form of salts of organic acids such as hydrochlorides, hydrobromides,or sulfates and the reaction of compounds of formula (II), optionally inform of their reactive derivatives, is performed with compounds (III) ina suitable, preferably inert, solvent such as aromatic hydrocarbons suchas benzene, toluene, xylene, halogenated hydrocarbons such asdichloromethane, chloroform, 1,2-dichloroethane, trichloroethylene, orethers such as diethyl ether, tetrahydrofuran, dioxane, glycol dimethylether, ethylacetate, acetonitrile or polar aprotic solvents such asdimethylsulfoxide, dimethylformamide or N-methylpyrrolildone as such inpure form or as mixtures of two or more thereof, wherein the reaction isoptionally carried out in the presence of an auxiliary base such asalkali metal carbonates, for example sodium carbonate, potassiumcarbonate, alkali metal hydrogen carbonates such as sodium hydrogencarbonate, potassium hydrogen carbonate, or organic bases such astriethylamine, ethyldiisopropylamine, tributylamine, N-methylmorpholineor pydridine, wherein a suitable excess of the compound of formula (III)can be used as a base, and in case of use of the compounds of formula(III) in form of their acid addition salts, the amount of the auxiliarybase is considered equivalent, and the reaction temperatures preferablylie between −40° C. and 180° C., especially between −10° C. and 130° C.,preferably at the boiling point of the solvent used.
 16. Methodaccording to claim 14, characterized in that according to method variant(b), the reaction of compounds (I), in which G is hydrogen, withcompounds according to formula (IV) can be carried out in an inertsolvent such as aromatic hydrocarbons for example, benzene, toluene,xylene, or ethers, for example, in tetrahydrofuran, dioxane, glycoldimethyl ether, or in ethylacetate, acetonitrile, ketones such asacetone, ethyl methyl ketone, in polar protic solvents such as alcoholssuch as ethanol, isopropanol, butanol, glycol monomethyl ether or polaraprotic solvents such as dimethylsulfoxide, dimethylformamide orN-methylpyrrolidone, wherein pure solvent as well as mixtures of two ormore of them can be used, and the reactions can be carried out in thepresence of bases, for example in the presence of the same as they canbe used according to the method variant (a) according to claim 15, and,in the case of the chlorides or bromides as compounds (IV), addition ofalkali metal iodides such as sodium iodide or potassium iodide occursand the reaction temperatures can vary between 0° C. and 180° C.,however, preferably between 20° C. and 130° C., depending on thereactivity of the educts.
 17. Compounds according to the general formula(I)

wherein G is hydrogen and the remaining substituents have the meaningsgiven in the claims 1-7.
 18. Compound or compound mixture according toone of the claims 1-13 and 17 for use in a therapeutic method fortreatment of the human or animal body or in a corresponding diagnosismethod.
 19. Compound or compound mixture for use in a therapeutic methodaccording to claim 18, characterized in that the therapeutic use is inconnection with cancerostatic or cytostatic or immunosuppressivetreatment, optionally in connection with suitable pharmaceuticallyacceptable adjuvants and carriers and/or one or more further activeingredients.
 20. Use of one or more compounds according to one of theclaims 1-13 and 17, including(E)-3-(3-pyridyl)-N-[2-(1-benzylpiperidine-4-yl)ethyl]-2-propenamidehydrochloride, for the preparation of a medicament for treatment of thehuman or animal body in the medical indications named above in claim 19.21. Use of one or more compounds according to one of the claims 1-13 and17, including(E)-3-(3-pyridyl)-N-[2-(1-benzylpiperidine-4-yl)ethyl]-2-propenamidehydrochloride, for the production of a medicament for cytostatictreatment of the human or animal body.
 22. Medicament with an amount ofone or more active ingredients according to one or more of the claims1-13 and 17, optionally in connection with a pharmaceutically acceptablecarrier, aside from toxicologically safe adjuvants, and/or incombination with other active ingredients,.
 23. Method for theproduction of a medicament according to claim 22, characterized in thatone or more of the compounds according to one or more of the claims 1-13and 17 are processed with suitable, pharmaceutically acceptable carriersand adjuvants to a finished medical form.
 24. Medicament according toclaim 22, characterized in that it is present in the form of a solid,peroral administration form as a tablet, capsule, coated tabletoptionally in sustained action or gastric fluid-resistant form, or as aliquid, peroral administration solution, suspension, effervescent tabletin the form of tabs or sachets, optionally in sustained action, ifpossible, or in gastric fluid-resistant form.
 25. Medicaments accordingto claim 22, characterized in that it is present in the form of asuitable injection or infusion preparation together with suitablepharmaceutically acceptable carriers and adjuvants, optionally insustained action form or as a parenteral depot medicinal form or implantor is used in the form of a concentrate, powder or lyophilisate and theparenteral dilution agent is optionally manufactured in the packagingseparately therefrom, wherein the mixing of both compounds with eachother or of the active ingredient with a common parenterally applicabledilution agent occurs immediately before use.
 26. Medicament accordingto claim 22, characterized in that it is present in the form of aninhalation therapeutic agent, for example, in the form of a spraytogether with suitable pharmaceutically acceptable propellants, carriersand adjuvents.
 27. Medicament according to claim 22, characterized inthat it is present in the form of a transdermal therapeutic system forsystemic treatment.
 28. Medicament according to claim 22, characterizedin that it is present in the form of a gastrointestinal therapeuticsystem for systemic treatment.
 29. Medicament according to claim 22,characterized in that it is present in the form of a salve, suspension,emulsion, a balm or plaster or in the form of an externally applicablesolution.
 30. Medicament according to claim 26 for administration bymeans of a controlled dosage aerosol or in the form of a dry powderdosage formulation.
 31. Medicament according to claim 22, characterizedin that it is present in the form of a rectal, genital, or transurethraladministration emulsion, a solution, a liposomal solution, an implant,suppository or a capsule.
 32. Medicament according to claim 22,characterized in that it is present in the form of a nasal, otologic orophthalmologic composition.
 33. Medicament according to claim 22 or 24,characterized in that it is present in the form of a buccally applicableform.
 34. Medicament according to claim 22 and 24, characterized in thata dosage unit for single administration contains 0.01 to 2.0 mg or0.1-10 or 20 mg active ingredient according to the claims 1-13 and 17.35. Medicament according to claim 26, characterized in that thepharmaceutically acceptable carrier and/or diluent is a propellantaerosol.
 36. Medicament according to claim 26 or 35, characterized inthat the propellant aerosol is tetrafluoroethane and/orheptafluoropropane and/or propane, butane, or dimethyl ether or mixturesthereof.
 37. Medicament according to claim 26, 35 or 36, characterizedin that the propellant aerosol contains surface active adjuvants. 38.Medicament according to claim 22 or 26, characterized in that itcontains glucose and/or lactose as a dry powder dosage.
 39. Substance orsubstance mixture according to claim 19 or 20, characterized in that thetherapeutic use is suitable in connection with the combination with afurther cytostatic agent or immunosuppressive agent.
 40. Medicamentaccording to claim 22 and 24, characterized in that it is present incombination with a further cytostatic agent or immunosuppressive agent,optionally in the form of separate dosage units in the pharmaceuticalpackage. 41.N-(4-diphenylmethyl-morpholin-2-ylmethyl)-3-(pyridin-3-yl)-acrylamide.